BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Germline missense variants in BRCA1 and BRCA2 genes, often classified as variants of uncertain significance (VUS), present challenges in assessing breast cancer risk.
• Establishing the clinical relevance of these variants is crucial for accurate risk assessment and management.

Purpose of the Study:

• To investigate the association between specific BRCA1 and BRCA2 missense variants and breast cancer risk across different ancestries.
• To determine the functional impact of identified variants on BRCA2 protein activity.

Main Methods:

• A large-scale breast cancer case-control study involving genotyping data from European and Asian populations.
• Analysis of 19 BRCA1 and 33 BRCA2 missense variants.
• Functional characterization of BRCA2 variants using quantitative assays.

Main Results:

• The BRCA2 c.9104A>C (p.Tyr3035Ser) and BRCA1 c.5096G>A (p.Arg1699Gln) variants were linked to moderately increased breast cancer risks in Europeans.
• The BRCA2 c.7522G>A (p.Gly2508Ser) and c.8187G>T (p.Lys2729Asn) variants showed moderate and low breast cancer risks in Asians, respectively.
• Functional assays revealed reduced BRCA2 activity for the p.Tyr3035Ser variant.

Conclusions:

• Specific BRCA2 missense variants influencing protein function confer clinically relevant, moderately increased breast cancer risks.
• These findings have potential implications for refining breast cancer risk management guidelines for individuals carrying these variants.