Identification of Genetic Variants Among Breast Cancer Patients and At-Risk Individuals: A Cohort Study in Sri Lanka.

Background Breast cancer remains a major global health challenge, as it is the most commonly diagnosed malignancy worldwide, particularly among women. Germline variants in cancer-predisposing genes play a critical role in breast cancers with familial origin.

Objectives To identify genetic variants in cancer-predisposing genes among breast cancer patients and individuals at risk in a selected cohort from two imaging facilities in the Central Province of Sri Lanka.

Design A genetic association study involving breast cancer confirmed patients, at-risk individuals, and healthy controls.

Methods Blood samples were collected from consenting patients, and genomic DNA was extracted from the samples and subjected to Next Generation Sequencing and Sanger sequencing. The inherited predisposition to breast cancer was evaluated to find genes associated with breast cancer using the Ion Torrent PGM platform followed by bioinformatics analysis.

Results Variants were detected in several high- and moderate-penetrance genes, including BRCA1 [c.3113A>G; p.Glu1038Gly], BRCA2 [c.6509A>G; p.Lys2170Arg; c.7879A>T; p.Ile2627Phe; c.5574_5577delAATT; p.Ile1859LysfsTer3], PALB2 [c.1592delT; p.Leu531fs], BRIP1 [c.2400C>T;], and in MRE11A [c.508C>A; p.Gln170Lys] genes. Among these, BRCA2 mutations and the PALB2 frameshift deletion were classified as pathogenic germline variants. The benign BRCA1 variant [c.3113A>G; p.Glu1038Gly] was the most frequent variant observed. Common missense variants included BRCA1 [c.3113A>G; p.Glu1038Gly; c.3548A>G; p.Lys1183Arg; c.2612C>T; p.Pro871Leu], BRCA2 [c.7397T>C; p.Val2466Ala], and ATM [c.5948A>G; p.Asn1983Ser], while frequently detected intronic variants were found in MUTYH [c.1468-40C>G;], PALB2 [c.3114-51T>A;], and NF1 [c.288+41G>A; c.328+37C>G;]. Pathogenic variants occurred in fewer than 10% of individuals in any group, and other variants were identified in different frequencies. Conclusion: Evaluation of germline variants in this cohort revealed the presence of pathogenic mutations and other variants with benign or uncertain significance. Three pathogenic variants, BRCA2 [c.6509A>G; c.7879A>T; c.5574_5577delAATT] and PALB2 [c.1592delT], were identified in high-risk genes important for breast cancer prediction. Identification of population-based variants may improve breast cancer screening and management in Sri Lanka.