Your weekly snapshot of clinically actionable genes from the ACMG Secondary Findings List.

Clinical Phenotype Summary:

The BRCA2 gene (NM_000059.3) is located on chromosome 13q13.1, encodes the breast cancer type 2 susceptibility protein, and contains 26 coding exons. Pathogenic variants in this gene are known to cause BRCA2-related cancer predisposition, which is inherited in an autosomal dominant fashion, and BRCA2-related Fanconi anemia, which is inherited in an autosomal recessive fashion.

BRCA2-related cancer predisposition is characterized by a significantly increased cumulative lifetime risk for:

• female breast cancer (55-69%)
• male breast cancer (1.8-7.1%)
• epithelial ovarian cancer (13-29%)
• pancreatic cancer (5-10%)
• prostate cancer (19-61%)
• melanoma
• gastric cancer (3.5%, with elevated risk in individuals with confirmed H. pylori infection)

BRCA2-related cancer predisposition is also associated with:

• a contralateral female breast cancer risk of up to 26% within 20 years of initial breast cancer diagnosis with no intervention; however, this risk is age-dependent and more significant with earlier age (prior to age 40) of first breast cancer diagnosis

Penetrance in individuals with BRCA2-related cancer predisposition is incomplete and variable expressivity is observed; therefore, cancer risks will differ based on individual and family history. Loss of function has been reported as the mechanism of disease for BRCA2-related cancer predisposition.

BRCA2-related Fanconi anemia is characterized by:

• progressive bone marrow failure
• adult-onset aplastic anemia
• pre- and postnatal growth deficiency
• abnormal skin pigmentation
• characteristic skeletal malformations
• impaired endocrine functioning

BRCA2-related Fanconi anemia can be established in a patient following cytogenetic testing of patient lymphocytes that demonstrate increased chromosomal breakage and radial forms following diepoxybutane and mitomycin C exposure.

Individuals with BRCA2-related Fanconi anemia are at an increased risk of malignancies with highest risk of:

• acute myelogenous leukemia
• early-onset solid tumors including head and neck squamous cell carcinoma
• non-melanoma skin cancer

Individuals of reproductive age are at 25% risk of having a child with Fanconi anemia with each pregnancy when both biological parents have a pathogenic variant in BRCA2. Biallelic loss of function, with at least one hypomorphic allele, has been reported as the mechanism of disease for BRCA2-related Fanconi anemia.

Unique Considerations:

• Published evidence suggests that both germline and somatic alterations in the BRCA2 gene predict sensitivity to chemotherapy agents that induce DNA damage and have been included in some indications for approved poly(ADP-ribose) polymerase (PARP) inhibitor therapies.

Clinical Resources:

• BRCA2 Clinician Management Resource + Understanding Your Results

Ambry Knows Genes:

Peer-Reviewed Publications:

• Combining multiplexed assays of variant effect for enhanced BRCA2 variant classification (Nature Communications, August 2026)
• An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance (NPJ Genomic Medicine, July 2023)
• Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel
• BRCA1-, BRCA2-, and PALB2-related Fanconi anemia: Scope to expand disease phenotypic features and predict breast cancer risk in heterozygotes

Scientific Presentations:

• Reduced penetrance BRCA1 and BRCA2 pathogenic variants in clinical germline genetic testing (AACR, April 2024)
• BRCA2 mutation carriers may present with primary brain tumors: A review of a multigene panel testing cohort

Scientific Posters:

• Women with breast and uterine cancer are at increased risk for hereditary cancer predisposition (SGO, March 2018)
• High-throughput characterization of BRCA1 and BRCA2 splicing defects (October 2016)
• Hereditary Risks of Male Breast Cancer in a Multi-Gene Panel Testing Cohort

To read more about Ambry’s research on this gene, visit the ‘Our Research’ dropdown on our website https://www.ambrygen.com/science.

Citations:

• Kuchenbaecker K et al. JAMA. 2017 Jun 20;317(23):2402-2416. PMID: 28632866
• Hu C et al. J Natl Cancer Inst. 2020 Dec 14;112(12):1231-124. PMID: 32091585
• Breast Cancer Association Consortium. N Engl J Med. 2021;384:428-439. PMID: 33471973
• Hu C et al. N Engl J Med. 2021 Feb 4; 384(5): 440–451. PMID: 33471974
• Tai Y et al. J Natl Cancer Inst. 2007 Dec 5;99(23):1811-4. PMID: 18056635
• Chen J et al. JNCI Cancer Spectr. 2020 Apr 23;4(4):pkaa029. PMID: 32676552
• Chaffee K et al. Genet Med. 2018 Jan;20(1):119-127. PMID: 28888541
• Hu C et al. JAMA. 2018 Jun 19;319(23):2401-2409. PMID: 29922827
• Li S, et al. (2022) J Clin Oncol 40(14):1529-1541. PMID: 35073151
• Yang R, et al. (2026) BMC Med 24(1). PMID: 38049803
• Usui Y, et al. (2023) N Engl J Med 388(13):1181-1190. PMID: 36988593
• Kim G et al. Clin Cancer Res. 2015 Oct 1;21(19):4257-61. PMID: 26187614
• Balasubramaniam S et al. Clin. Cancer Res., 2017 Dec;23:7165-7170. PMID: 28851811
• Mehta P et al. Fanconi Anemia. 2002 Feb 14 [updated 2021 Jun 3]. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. PMID: 20301575
• García-de-Teresa B et al. Genes (Basel). 2020 Dec 21;11(12):1528, 2020. PMID: 33371494

Ambry Genetics Gene-Disease Validity Scheme

Each week, we explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early.

To learn more about the ACMG Secondary Findings list, click here.

To read all previous Gene Scene emails, click here.