Evidence map›Paper›PMID 39570271›Full record

ArticleGenetics in medicine : official journal of the American College of Medical Genetics2025

Multi-ethnic heterozygote frequencies of cancer susceptibility genes to inform counseling of reproductive risk.

Jacquelyn Powers, Heather Wachtel, Erica Trujillo, Heena Desai, Ryan Hausler, Laura Conway, Bradley Wubbenhorst, Penn Medicine BioBank, Regeneron Genetics Center, Susan M Domchek and 2 more

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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

12 authors.

Jacquelyn PowersDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Heather WachtelDepartment of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Erica TrujilloDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Heena DesaiDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Ryan HauslerDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Laura ConwayDepartment of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
Bradley WubbenhorstDivision of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Penn Medicine BioBank
Regeneron Genetics Center
Susan M DomchekDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Katherine L NathansonDepartment of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Kara N MaxwellDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA. Electronic address: kara.maxwell@pennmedicine.upenn.edu.

Funding

A genotype-phenotype study of germline succinate dehydrogenase pathogenic variantsK08CA270385 · NCI · UNIVERSITY OF PENNSYLVANIA · PI Heather Wachtel · 2022 to 2026
$967k
A genotype-phenotype study of tumors from patients with inherited mutations in DNA repair genesK08CA215312 · NCI · UNIVERSITY OF PENNSYLVANIA · PI MAXWELL, KARA N · 2018 to 2022
$924k
NCI NIH HHS K08 CA215312NCI NIH HHS K08 CA270385
6 · The paper itself

Abstract

purposePathogenic germline variants (PGVs) in a subset of cancer predisposition genes (CPGs) are associated with adult-onset autosomal dominant (AD) cancer susceptibility and life-limiting autosomal recessive (AR) disease. Counseling in adult cancer genetics clinics regarding reproductive risk for PGV heterozygotes is limited.

methodsEstimated heterozygote frequencies across ancestries were calculated for AD CPGs with AR risk (ATM, BRCA1, BRCA2, BRIP1, FH, NBN, MLH1, MSH2, MSH6, PMS2, RAD51C, SDHA, SDHB, and SDHD) from gnomADv.3.0, the Penn Medicine Biobank, and FLOSSIES.

resultsAverage frequencies of heterozygotes with PGVs across ancestries for BRCA1 and BRCA2 were 0.33% ± 0.41% and 0.43% ± 0.36%, with variability cross-ancestry from 0.06% to 1.32% and 0.17% to 1.29%, respectively. ATM had the next highest PGV heterozygote frequency (0.31% ± 0.12%) and SDHD the lowest (0.01% ± 0.01%) average PGV heterozygote frequency. Heterozygote PGV frequencies from gnomAD were similar as cancer-free individuals in Penn Medicine Biobank and higher than in the FLOSSIES data. DISCUSSION: Heterozygote frequency estimates for AD CPGs that cause AR disease provides information to facilitate discussions regarding reproductive risk. Future studies are needed to assess whether utilization of these data will influence couples' reproductive risk planning.

Indexed as

Genetic CounselingGenetic Predisposition to DiseaseGerm-Line MutationNeoplasmsAdultBRCA1 ProteinBRCA2 ProteinEthnicityFemaleGene FrequencyGenetic TestingHeterozygoteHumansMaleBRCA1 ProteinBRCA2 ProteinAutosomal dominant cancer susceptibilityAutosomal recessive conditionsGenetic counselingHeterozygote frequencyReproductive counseling

Identifiers

PMID39570271
PMCPMC11717631

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.