Cancer is characterized by complex interactions across genetic, cellular, and microenvironmental scales. However, a quantitative understanding of how these interactions shape clinical trajectories remains limited. Here, we present a multi-scale single-cell dataset from 184 treatment-naive acute myeloid leukemia (AML) patients spanning all major genetic subtypes, together with an analytical framework to dissect interactions across biological scales. We show that distinct clinical outcomes are encoded by specific cross-scale, cross-compartment interactions present at diagnosis: response to induction therapy is governed by interactions between genetic alterations and leukemic differentiation state; relapse following chemotherapy is associated with non-genetic programs linked to metabolism; and relapse after allogeneic stem cell transplantation is driven by interactions between the immune microenvironment and residual healthy hematopoiesis. Together, our study provides a framework to resolve intra- and inter-patient heterogeneity in cancer and supports a model in which clinical trajectories in AML emerge from defined interactions across biological scales.

Myeloid neoplasms with germline predisposition have been recognized increasingly over the past decade with numerous newly described disorders. Penetrance, age of onset, phenotypic heterogeneity, and somatic driver events differ widely among these conditions and sometimes even within family members with the same variant, making risk assessment and counseling of these individuals inherently difficult. In this review, we will shed light on high malignant penetrance (e.g., CEBPA, GATA2, SAMD9/SAMD9L, and TP53) versus variable malignant penetrance syndromes (e.g., ANKRD26, DDX41, ETV6, RUNX1, and various bone marrow failure syndromes) and their clinical features, such as variant type and location, course of disease, and prognostic markers. We further discuss the recommended management of these syndromes based on penetrance with an emphasis on somatic aberrations consistent with disease progression/transformation and suggested timing of allogeneic hematopoietic stem cell transplant. This review will thereby provide important data that can help to individualize and improve the management for these patients.

The genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy.

The ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) focuses on the development of curation rules for variants in several genes that confer risk for myeloid malignancies, such as GATA2. The absence of a defined GATA2 deficient phenotype description challenges the direct application of disease-related ACMG-AMP codes. Therefore, the MM-VCEP is drafting a consensus definition of the GATA2 deficiency based on the phenotypic presentation of individuals from multiple centers worldwide using a modified Delphi approach. A detailed questionnaire including to collect phenotypic data on individuals with deleterious germline GATA2 variants. Individual phenotype data were collected on 110 phenotypes previously attributed to GATA2 deficiency from 437 individuals (340 individuals with confirmed germline variants, and 97 with suspected germline variants) from 17 centers across seven countries, representing the largest patient cohort ever assembled. The most frequently reported phenotypes were pancytopenia (36%), myelodysplastic syndrome (MDS, 59%), and human papilloma virus (HPV)-related warts (53%), with some variation in frequencies by age. These frequencies will be compared to those seen in normal populations, with the UKBiobank serving as the comparator for those over 40 years old. The MM-VCEP plans to develop a weighted scoring system of clinical and laboratory parameters that will define GATA2 deficiency phenotype, and with this consensus phenotype description, the MM-VCEP will complete its GATA2 variant curation rules The ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) focuses on the development of curation rules for variants in several genes that confer risk for myeloid malignancies, such as GATA2. The absence of a defined GATA2 deficient phenotype description challenges the direct application of disease-related ACMG-AMP codes. Therefore, the MM-VCEP is drafting a consensus definition of the GATA2 deficiency based on the phenotypic presentation of individuals from multiple centers worldwide using a modified Delphi approach. A detailed questionnaire including to collect phenotypic data on individuals with deleterious germline GATA2 variants. Individual phenotype data were collected on 110 phenotypes previously attributed to GATA2 deficiency from 437 individuals (340 individuals with confirmed germline variants, and 97 with suspected germline variants) from 17 centers across seven countries, representing the largest patient cohort ever assembled. The most frequently reported phenotypes were pancytopenia (36%), myelodysplastic syndrome (MDS, 59%), and human papilloma virus (HPV)-related warts (53%), with some variation in frequencies by age. These frequencies will be compared to those seen in normal populations, with the UKBiobank serving as the comparator for those over 40 years old. The MM-VCEP plans to develop a weighted scoring system of clinical and laboratory parameters that will define GATA2 deficiency phenotype, and with this consensus phenotype description, the MM-VCEP will complete its GATA2 variant curation rules

There remain gaps in our knowledge of hereditary and sporadic causes of hematological malignancy (HM) and bone marrow failure (BMF) that prevent optimal diagnosis, disease surveillance and treatment. Here we report the discovery of ERG as a novel predisposition gene for BMF and HM. ERG is a known oncogene, typically via gene-fusions, leading to dysregulated ERG overexpression in blood and solid cancers. We identified a germline ERG ETS domain variant p.Y373C segregating with thrombocytopenia in a mother, who progressed to AML (27 yr) and then therapy-related MDS (35 yr), and in her 2 sons. All three showed copy neutral loss of heterozygosity of all or part of chromosome 21q, including the ERG locus, with the oldest son showing at least 2 somatic genetic rescue (SGR) events. The possibility of causal RUNX1 variants were ruled out, with the smallest somatic cnLOH event beginning within the RUNX1 gene, but not encompassing the RUNT domain where the majority of pathogenic missense variants are located. ERG, a highly constrained gene (LOEUF <0.33), is critical for definitive hematopoiesis, adult hematopoietic stem cell (HSC) function and platelet maintenance. An identical corresponding heterozygous germline variant (p.Y343C) in ERG’s closest gene by homology, FLI1, causes platelet-type bleeding disorder-21 (BDPLT21, OMIM #617443). Through global collaborations, we have identified 15 heterozygous variants in the ERG gene, 13 of which are missense and 2 truncating variants, in 17 individuals with cytopenia and/or HM (mainly myeloid) or lymphedema (Table). Onset of hematological symptoms ranged from birth to 38 years for truncating and constrained ETS domain variants. Of these 15 variants, 12 have been confirmed germline including 2 de novo. Only 4 meiotic transmissions are observed. None of the missense variants in the highly conserved ETS domain of ERG which mediates DNA binding, protein-protein interactions and nuclear localization, are present in gnomAD. We have functionally characterized 19 ERG variants, 12 potentially pathogenic, 1 known mouse pathogenic variant and 3 population controls demonstrating that most ETS domain missense variants display loss-of-function (LOF) characteristics disrupting transcriptional transactivation (Figure), DNA-binding and/or nuclear localization in vitro. Robust preliminary data from ex vivo models of ERG overexpression in mouse fetal liver cells in tissue culture (cytokine-independence), a mouse transplant assay and previous germline mutant Erg mouse models are concordant with ETS domain missense variants being LOF compared to wildtype ERG and benign controls. Together, these data provide clinical, in vitro and ex vivo functional studies implicating LOF variants in hematological disease predisposition. LOF ERG mutations also occur in sporadic cases of HM. Recently, as part of a Genomics England Research Consortium population study, 4 truncating ERG variants were described in 7 individuals across 4 families with 3 meiotic transmissions and a de novo case with primary lymphedema (1) and we add 2 novel missense variants here. One patient showed SGR across the ERG locus in blood. Blood phenotypes were not described. Our results demonstrate that germline ERG variants predispose to diverse cytopenia, BMF and HM in both children and adults. In our family mentioned above, the mother received an unrelated alloHSCT due to t-MDS while her 2 sons with cytopenias continue to be monitored. The natural history of this new syndrome will require careful identification of germline lesions with additional longitudinal studies in more patients and families needed. This ERG syndrome parallels GATA2 deficiency syndrome (HM and lymphedema) and RUNX1 Familial Platelet disorder-myeloid malignancy (thrombocytopenia and HM). Like the well-known disease genes GATA2 and RUNX1, ERG is also a member of the transcription factor heptad involved in HSC maintenance and differentiation. ERG adds to a growing list of genes whose unregulated expression contributes to HM and other cancers. Identification of causal germline ERG variants like those outlined in this study, has direct clinical implications for patient and family management including diagnosis, counselling, surveillance and treatment strategies such as selection of bone marrow transplant donors and potential for targeted therapies including gene and cell therapy. Reference 1. Greene D et al. Nat.Med. 29:679-688 2023

This chapter includes answers to practice-based questions with a case study covering the new principles of diagnosis, classification, treatment, and outcomes in Familial Myeloid Neoplasms. Familial myeloid neoplasms are a heterogeneous group of disorders wherein the presence of a germline gene variant leads to a heritable risk of developing myelodysplastic syndromes (MDS), acute myeloid leukemia, or myeloproliferative neoplasms. The chapter outlines the approach to identifying patients with germline predisposition syndromes and identifies the key components to managing the unique needs of these patients. Any patient diagnosed with MDS or aplastic anemia under age 40 should undergo clinical testing to identify possible germline variants. It is also important to recognize that familial predisposition syndromes occur across the entire age spectrum. The selection of appropriate confirmatory germline genetic testing for patients with a suspected familial syndrome is a crucial aspect of patient management.

Inherited bone marrow failure (BMF) syndromes are genetically diverse — more than 100 genes have been associated with those syndromes and the list is rapidly expanding. Risk assessment and genetic counseling of patients with recently discovered BMF syndromes is inherently difficult as disease mechanisms, penetrance, genotype-phenotype associations, phenotypic heterogeneity, risk of hematologic malignancies and clonal markers of disease progression are unknown or unclear. This review aims to shed light on recently described BMF syndromes with sparse concise data and with an emphasis on those associated with germline variants in ADH5/ALDH2, DNAJC21, ERCC6L2 and MECOM. This will provide important data that may help to individualize and improve care for these patients.

Inherited hematologic malignancies are linked to a heterogenous group of genes, knowledge of which is rapidly expanding using panel-based next-generation sequencing (NGS) or whole-exome/whole-genome sequencing. Importantly, the penetrance for these syndromes is incomplete, and disease development, progression or transformation has critical clinical implications. With the earlier detection of healthy carriers and sequential monitoring of these patients, clonal hematopoiesis and somatic driver variants become significant factors in determining disease transformation/progression and timing of (preemptive) hematopoietic stem cell transplant in these patients. In this review, we shed light on the detection of probable germline predisposition alleles based on diagnostic/prognostic ‘somatic’ NGS panels. A multi-tier approach including variant allele frequency, bi-allelic inactivation, persistence of a variant upon clinical remission and mutational burden can indicate variants with high pre-test probability. We also discuss the shared underlying biology and frequency of germline and somatic variants affecting the same gene, specifically focusing on variants in DDX41, ETV6, GATA2 and RUNX1. Germline variants in these genes are associated with a (specific) pattern or over-/underrepresentation of somatic molecular or cytogenetic alterations that may help identify the underlying germline syndrome and predict the course of disease in these individuals. This review is based on the current knowledge about somatic drivers in these four syndromes by integrating data from all published patients, thereby providing clinicians with valuable and concise information.

Background Patients with an underlying telomere biology disorder (TBD) have variable clinical presentations and can be challenging to diagnose clinically. A genomic diagnosis for patients presenting with TBD is vital for optimal treatments. Unfortunately, many variants identified during diagnostic testing are variants of uncertain significance (VOUS). This complicates management decisions, delays treatment and risks non-uptake of a potentially curative therapies. Improved application of functional genomic evidence may reduce VOUS classifications. Methods We systematically searched the literature for published functional assays interrogating TBD gene variants. Where possible, established likely benign/benign and likely pathogenic/pathogenic variants were used to estimate the assay sensitivity, specificity, positive predictive value, negative predictive value and odds of pathogenicity. Results 3131 articles were screened and 152 met inclusion criteria. Sufficient data to enable a PS3/BS3 recommendation was available for TERT variants only. We recommend PS3 and BS3 can be applied at a moderate and supportive level respectively. PS3/BS3 application was limited by a lack of assay standardisation and limited inclusion of benign variants. Conclusions Further assay standardisation and assessment of benign variants is required for optimal use of the PS3/BS3 criterion for TBD gene variant classification.

Due to differences in the protein folding mechanisms, it is exceedingly rare for amyloid light chain (AL) amyloidosis and monoclonal gammopathy of renal significance (MGRS) to coexist. We herein report the first case of concurrent AL amyloidosis and a subclass of MGRS, light chain proximal tubulopathy (LCPT). The 53-year-old female was diagnosed with smoldering myeloma immunoglobulin G kappa and AL amyloidosis with deposits in fat and gastrointestinal tissue. The kidney biopsy did not show amyloid deposits but electron microscopy revealed the presence of LCPT with crystal formation in proximal tubular epithelial cells. This case illustrates the complex pathophysiology of protein deposition in monoclonal gammopathies.

Sequence variant interpretation (SVI) is a formal process by which gene variants are classi fi ed as pathogenic (P), likely pathogenic (LP), variant of uncertain signi fi cance, likely benign (LB), or benign (B). The classi fi cations, based on the 28 criteria de fi ned by the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), 1 are intended to undergo gene-speci fi c modi fi cation facilitated by different Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEPs). The ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) is charged with developing curation rules for genes in which variants confer risk for myeloid malignancies, starting with RUNX1 . 2,3 To re fl ect the continual updates from current literature and ClinVar submissions accu-rately, ClinGen advocates reevaluation of variant curation speci fi cations on a regular basis. In response to this recommendation coupled with additional re fi nement of ACMG/AMP criteria by the ClinGen SVI Working Group, the MM-VCEP has updated its RUNX1 curation rules to increase accuracy of curation in the fi elds of hematology, genetics, and pathology while optimizing clinical assessments of patients undergoing testing for inherited predisposition (Table 1; Figure 1A; supplemental case studies).

Broader genetic screening has led to the growing recognition of the role of germline variants associated with adult bone marrow failure (BMF) and myeloid neoplasia (MN) not exclusively in children and young adults. In this study, we applied a germline variant panel to 3008 adult BMF and MN cases to assess the importance of germline genetics and its impact on disease phenotype and prognosis. In our cohort, up to 9.7% of BMF and 5.3% of MN cases carried germline variants. Our cohort also included heterozygous carriers of recessive traits, suggesting they contribute to the risk of BMF and MN. By gene category, variants of Fanconi anemia gene family represented the highest-frequency category for both BMF and MN cases, found in 4.9% and 1.7% cases, respectively. In addition, about 1.4% of BMF and 0.19% of MN cases harbored multiple germline variants affecting often functionally related genes as compound heterozygous. The burden of germline variants in BMF and MN was clearly associated with acquisition of monosomy 7. While BMF cases carrying germline variants showed similar overall survival as compared to the wild-type (WT) cases, MN cases with germline variants experienced a significantly shorter overall survival as compared to WT cases.

The frequency of pathogenic/likely pathogenic (P/LP) germ line variants in patients with myelodysplastic syndrome (MDS) diagnosed at age 40 years or less is 15% to 20%. However, there are no comprehensive studies assessing the frequency of such variants across the age spectrum. We performed augmented whole-exome sequencing of peripheral blood samples from 404 patients with MDS and their related donors before allogeneic hematopoietic stem cell transplantation. Single-nucleotide and copy number variants in 233 genes were analyzed and interpreted. Germ line status was established by the presence of a variant in the patient and related donor or for those seen previously only as germ line alleles. We identified P/LP germ line variants in 28 of 404 patients with MDS (7%), present within all age deciles. Patients with P/LP variants were more likely to develop higher-grade MDS than those without (43% vs 25%; P = .04). There was no statistically significant difference in outcome parameters between patients with and without a germ line variant, but the analysis was underpowered. P/LP variants in bone marrow failure syndrome genes were found in 5 patients aged less than 40 years, whereas variants in DDX41 (n = 4), telomere biology disorder genes (n = 2), and general tumor predisposition genes (n = 17) were found in patients aged more than 40 years. If presumed germ line variants were included, the yield of P/LP variants would increase to 11%, and by adding suspicious variants of unknown significance, it would rise further to 12%. The high frequency of P/LP germ line variants in our study supports comprehensive germ line genetic testing for all patients with MDS regardless of their age at diagnosis.

Purpose: The American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines for germline variant interpretation are implemented as a broad framework by standardizing variant interpretation. These rules were designed to be specified, but this process has not been performed for most of the 200 genes associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias. Because guidelines on how to perform these gene specifications are lacking, variant interpretation is less reliable and reproducible. Methods: We have used a variety of methods such as calculations of minor allele frequencies, quasi-case???control studies to establish thresholds, proband counting, and plotting of receiver operating characteristic curves to compare different in silico prediction tools to design recommendations for variant interpretation. Results: We herein provide practical recommendations for the creation of thresholds for minor allele frequencies, in silico predictions, counting of probands, identification of functional domains with minimal benign variation, use of constraint Z-scores and functional evidence, prediction of nonsense-mediated decay, and assessment of phenotype specificity. Conclusion: These guidelines can be used by anyone interpreting variants associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias to develop criteria for reliable, accurate, and reproducible germline variant interpretation. ?? 2021 by American College of Medical Genetics and Genomics. Published by Elsevier Inc.

The Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP; https://clinicalgenome.org/affiliation/50034/) was established by the American Society of Hematology and ClinGen and is supported since 2021 by the National Cancer Institute to provide curation rules for genes in which variants confer risk to myeloid malignancies. The MM-VCEP is currently focused on developing and refining curation rules for RUNX1, GATA2, and DDX41. In 2019, the MM-VCEP published specifications for RUNX1 variant curation, which were updated in 2021 and are pending publication. Informed by these its version 2 updates, the MM-VCEP actively curates RUNX1 variants deposited into ClinVar. The group is also initiating the specification of variant curation rules for DDX41, the gene most commonly driving inherited adult-onset myeloid malignancies. To create rule specifications for GATA2 variant curation, the MM-VCEP has embarked on a project to define the GATA2 deficiency phenotype utilizing data from multiple centers. The MM-VCEP is employing a modified Delphi method to define a consensus-based phenotypic description of GATA2 deficiency. The MM-VCEP has assembled, and is now analyzing, patient-level genotype and phenotype data from 446 individuals, 339 with confirmed germline GATA2 mutations and 107 with suspected germline variants, from 17 centers in 7 countries globally, representing the largest compilation of GATA2 deficiency data to date, and the only one to assemble data from multiple centers. We aim to soon develop an evidence-based definition of the GATA2-deficient phenotype. Ultimately, through our concerted efforts, the MM-VCEP aims to facilitate consistent gene variant curation globally, to advance a deeper understanding of myeloid malignancies. The Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP; https://clinicalgenome.org/affiliation/50034/) was established by the American Society of Hematology and ClinGen and is supported since 2021 by the National Cancer Institute to provide curation rules for genes in which variants confer risk to myeloid malignancies. The MM-VCEP is currently focused on developing and refining curation rules for RUNX1, GATA2, and DDX41. In 2019, the MM-VCEP published specifications for RUNX1 variant curation, which were updated in 2021 and are pending publication. Informed by these its version 2 updates, the MM-VCEP actively curates RUNX1 variants deposited into ClinVar. The group is also initiating the specification of variant curation rules for DDX41, the gene most commonly driving inherited adult-onset myeloid malignancies. To create rule specifications for GATA2 variant curation, the MM-VCEP has embarked on a project to define the GATA2 deficiency phenotype utilizing data from multiple centers. The MM-VCEP is employing a modified Delphi method to define a consensus-based phenotypic description of GATA2 deficiency. The MM-VCEP has assembled, and is now analyzing, patient-level genotype and phenotype data from 446 individuals, 339 with confirmed germline GATA2 mutations and 107 with suspected germline variants, from 17 centers in 7 countries globally, representing the largest compilation of GATA2 deficiency data to date, and the only one to assemble data from multiple centers. We aim to soon develop an evidence-based definition of the GATA2-deficient phenotype. Ultimately, through our concerted efforts, the MM-VCEP aims to facilitate consistent gene variant curation globally, to advance a deeper understanding of myeloid malignancies.

GATA2 deficiency syndrome (G2DS) is a rare autosomal dominant genetic disease predisposing to a range of symptoms, of which myeloid malignancy and immunodeficiency including recurrent infections are most common. In the last decade since it was first reported, there have been over 480 individuals identified carrying a pathogenic or likely pathogenic germline GATA2 variant with symptoms of G2DS, with 240 of these confirmed to be familial and 24 de novo. For those that develop myeloid malignancy (75% of all carriers with G2DS disease symptoms), the median age of onset is 17 years (range 0-78 years) and myelodysplastic syndrome is the first diagnosis in 75% of these cases with acute myeloid leukemia in a further 9%. All variant types appear to predispose to myeloid malignancy and immunodeficiency. Apart from lymphedema in which haploinsufficiency seems necessary, the mutational requirements of the other less common G2DS phenotypes is still unclear. These predominantly loss-of-function variants impact GATA2 expression and function in numerous ways including perturbations to DNA binding, protein structure, protein:protein interactions, and gene transcription, splicing, and expression. In this review, we provide the first expert-curated ACMG/AMP classification with codes of published variants compatible for use in clinical or diagnostic settings.

Background: Germline predisposition is increasingly being recognised in myeloid neoplasms (MN) including primary myelodysplastic syndrome. An unequivocal diagnosis of germline predisposition carries actionable considerations for patient management including donor stem cell source for allogeneic transplantation, dose-reduction of conditioning regimes and screening for extra-hematological disease (such as pulmonary abnormalities in patients with telomere biology disorders). In addition, the identification of MDS predisposition syndromes can avoid misdiagnosis (for example, distinguishing idiopathic thrombocytopenic purpura from thrombocytopenia due to RUNX1 germline variant). However, the prevalence of pathogenic germline variants (PGVs) in unselected pMDS patients presenting at older age remains unknown.

The majority of studies assessing the contribution of pathogenic germline variants (PGVs) to cancer predisposition have focused on patients with single cancers. We analyzed 45 known cancer predisposition genes (CPGs) in germline samples of 202 patients with hematological malignancies (HMs) plus one or more other independent cancer managed at major tertiary medical centers on two different continents. This included 120 patients with therapy-related myeloid neoplasms (t-MNs), where the HM occurred after cytotoxic treatment for a first malignancy, and 82 patients with multiple cancers in which the HM was not preceded by cytotoxic therapy (MC-HM). Using American College of Medical Genetics/Association for Molecular Pathology variant classification guidelines, 13% of patients had PGVs, most frequently identified in CHEK2 (17% of PGVs), BRCA1 (13%), DDX41 (13%), and TP53 (7%). The frequency of PGVs in MC-HM was higher than in t-MN, although not statistically significant (18 vs. 9%; p = 0.085). The frequency of PGVs in lymphoid and myeloid HM patients was similar (19 vs. 17.5%; p > 0.9). Critically, patients with PGVs in BRCA1, BRCA2 or TP53 did not satisfy current clinical phenotypic criteria for germline testing. Our data suggest that a personal history of multiple cancers, one being a HM, should trigger screening for PGVs.