MSH2 – Hereditary Breast Carcinoma

Germline MSH2 variants have been detected in familial breast cancer cohorts by next-generation and panel-based sequencing, although at low frequency. In a Lebanese whole-exome sequencing study of 45 familial breast cancer patients, one patient harbored c.1182T>G (p.Phe394Leu) in MSH2 (PMID:28202063). Subsequent multigene analyses in 460 Asian probands and in 205 BRCA1/2-wild-type cancer patients identified additional MSH2 pathogenic variants in single cases each (PMID:30875412; PMID:34371384). A targeted panel in 101 Egyptian familial breast cancer patients also reported MSH2 deleterious alleles in one subject (PMID:36672847). Across these four independent series, five unrelated probands carried germline MSH2 variants; no segregation data in extended families have been reported.

MSH2 encodes a core mismatch repair protein; extensive experimental data in yeast and murine systems demonstrate that Msh2 deficiency leads to mutator phenotypes, reduced repair complex stability, increased spontaneous mutation rates, and impaired apoptosis following DNA damage. Heterozygous loss or dominant-negative MSH2 alleles confer elevated genomic instability and tumor susceptibility in vivo (PMID:10077621; PMID:10097137). These functional assays support a haploinsufficiency mechanism but lack breast tissue–specific modelling.

While germline MSH2 pathogenic variants are rare in hereditary breast carcinoma, their presence across multiple cohorts and concordant DNA repair defects suggest a contributory role. Further segregation studies and breast-specific functional models are warranted to clarify penetrance and guide clinical testing.

Key Take-home: MSH2 screening may marginally enhance familial breast cancer risk stratification, but evidence remains limited without segregation confirmation.

References

• BMC medical genomics • 2017 • Next-generation sequencing in familial breast cancer patients from Lebanon. PMID:28202063
• 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
• ESMO open • 2021 • Impact of deleterious variants in other genes beyond BRCA1/2 detected in breast/ovarian and pancreatic cancer patients by NGS-based multi-gene panel testing: looking over the hedge. PMID:34371384
• 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
• Proceedings of the National Academy of Sciences of the United States of America • 1999 • Mutator phenotypes of yeast strains heterozygous for mutations in the MSH2 gene. PMID:10077621
• Proceedings of the National Academy of Sciences of the United States of America • 1999 • Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine. PMID:10097137

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