PMS2 – Hereditary Breast Carcinoma

PMS2 (HGNC:9122) encodes a key component of the MutLα complex in DNA mismatch repair. Germline PMS2 variants are well‐established in Lynch syndrome, and emerging data suggest a role in hereditary breast carcinoma (MONDO:0016419). Multigene panel studies have identified PMS2 alterations in breast cancer–susceptible cohorts beyond BRCA1/2.

In a real‐world Asian cohort of 460 probands with suspected hereditary breast cancer (HBC), multigene testing detected non‐BRCA1/2 pathogenic variants in 33 individuals (7.2%), including PMS2 (PMID:30875412). A review of 81 Latin American studies confirmed PMS2 among 12 HBC–related genes, though individual carrier counts were low (PMID:31658756). In a Tunisian series of BRCA1/2‐negative families, rare PMS2 copy number variants were observed in 9 cases (PMID:33503040). A Chinese familial breast cancer review similarly listed PMS2 among 16 susceptibility genes, with yet unquantified prevalence (PMID:34926254).

Inheritance is consistent with an autosomal dominant pattern, as seen in Lynch syndrome, but specific segregation data in breast cancer families are lacking. No extended pedigrees have reported multiple affected relatives with cosegregating PMS2 variants in the context of breast carcinoma.

Functional evidence for PMS2 in breast tumorigenesis is indirect: PMS2 haploinsufficiency impairs DNA repair fidelity and increases genomic instability, a known driver of malignancy. To date, no breast‐specific cellular or animal models have been published. High rates of variants of uncertain significance in panels (up to 44.5%) underscore the need for functional assays in PMS2.

Conflicting evidence is minimal, but the paucity of segregation and functional data limits definitive association. Larger cohorts and dedicated functional studies are needed to clarify the penetrance of PMS2 variants for breast cancer.

Overall, PMS2 has limited clinical validity for hereditary breast carcinoma: pathogenic variants are rare but may explain a small fraction of cases after BRCA1/2 testing. Inclusion of PMS2 in guideline‐based multigene panels can modestly improve diagnostic yield in high-risk patients.

Key take-home: While PMS2 pathogenic variants contribute to <1% of hereditary breast carcinoma cases, their detection influences surveillance and management when BRCA1/2 mutations are absent.

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
• PloS One • 2021 • Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia. PMID:33503040
• Frontiers in Oncology • 2021 • Familial Breast Cancer: Disease Related Gene Mutations and Screening Strategies for Chinese Population. PMID:34926254

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