MSH6 – Hereditary Breast Carcinoma

MSH6 encodes the MutS homolog 6 protein, a key component of DNA mismatch repair. Germline heterozygous variants in DNA repair genes, including MSH6, have been implicated in hereditary breast carcinoma (MSH6; Hereditary Breast Carcinoma).

In an Asian multi-ethnic cohort of 460 probands with suspected hereditary breast cancer, multigene testing beyond BRCA1/2 identified 33 non-BRCA1/2 pathogenic mutations, among which MSH6 was represented (PMID:30875412). A Latin American review reported a specific MSH6 missense variant c.2419G>A (p.Glu807Lys) in early-onset breast cancer patients (PMID:31658756).

Further, in a Guatemalan unselected series (n=664), moderate-penetrance genes including MSH6 contributed to an 11% overall pathogenic variant rate in breast cancer cases (PMID:34196900). An Egyptian familial cohort (n=101) similarly detected MSH6 among 27 deleterious germline mutations, emphasizing its role in familial breast cancer predisposition (PMID:36672847). The recurrent c.2419G>A (p.Glu807Lys) illustrates its occurrence across diverse populations.

Inheritance is autosomal dominant. No large segregation studies in breast cancer families have been reported, limiting familial linkage, and no affected relatives with proven MSH6 segregation have been documented to date.

Functional assays in human cancer cell lines deficient in MSH6 show a 50- to 750-fold increase in spontaneous mutation rates relative to proficient lines, consistent with haploinsufficiency leading to mismatch repair deficiency and genomic instability (PMID:9054582).

Collectively, identification of recurrent MSH6 pathogenic variants in multiple hereditary breast carcinoma cohorts and concordant mechanistic data support a Moderate level of clinical validity. Functional studies corroborate the mutator phenotype. Key take-home: Incorporation of MSH6 into multigene panels enhances risk stratification for hereditary breast carcinoma beyond BRCA1/2.

References

• PloS One • 2019 • Discoveries beyond BRCA1/2: Multigene testing in an Asian multi-ethnic cohort suspected of hereditary breast cancer syndrome in the real world. PMID:30875412
• Genes • 2019 • Landscape of Germline Mutations in DNA Repair Genes for Breast Cancer in Latin America: Opportunities for PARP-Like Inhibitors and Immunotherapy. PMID:31658756
• Breast Cancer Research and Treatment • 2021 • Germline variants in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer. PMID:34196900
• Genes • 2022 • Frequency of Pathogenic Germline Mutations in Early and Late Onset Familial Breast Cancer Patients Using Multi-Gene Panel Sequencing: An Egyptian Study. PMID:36672847
• Carcinogenesis • 1997 • Mutation rate at the hprt locus in human cancer cell lines with specific mismatch repair-gene defects. PMID:9054582

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