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. 2025 Jan;27(1):101246.
doi: 10.1016/j.gim.2024.101246. Epub 2024 Nov 21.

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

Jacquelyn Powers  1 , Heather Wachtel  2 , Erica Trujillo  1 , Heena Desai  1 , Ryan Hausler  1 , Laura Conway  3 , Bradley Wubbenhorst  4 ; Penn Medicine BioBank; Regeneron Genetics Center; Susan M Domchek  5 , Katherine L Nathanson  6 , Kara N Maxwell  7
Collaborators, Affiliations

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

Jacquelyn Powers et al. Genet Med. 2025 Jan.

Abstract

Purpose: Pathogenic 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.

Methods: Estimated 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.

Results: Average 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.

Keywords: Autosomal dominant cancer susceptibility; Autosomal recessive conditions; Genetic counseling; Heterozygote frequency; Reproductive counseling.

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Conflict of interest statement

Conflict of Interest The authors declare no conflicts of interest.

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