MUS81 – Familial Breast Cancer

MUS81 has emerged as a promising candidate gene in the etiology of familial breast cancer. Multiple independent studies, including case reports and multi‐patient analyses, have supported the role of MUS81 in DNA repair and cancer predisposition, placing this gene-disease association within a strong clinical framework (PMID:32443704).

In a pivotal study, a recurrent germline variant, c.1292G>A (p.Arg431His), was identified in patients with familial breast cancer. This variant was shown to segregate with disease in two families, with a total of four affected relatives, providing key segregation evidence (PMID:32443704). Additional multi-patient investigations further supported the association by identifying risk-modifying SNPs in MUS81 among breast cancer cases (PMID:19714462).

Genetic evidence for this association is bolstered by the recurrence of the c.1292G>A (p.Arg431His) variant and its demonstration in multiple family-based studies. The variant is consistently observed in familial cases and shows a clear pattern of co-segregation with breast cancer across affected individuals (PMID:32443704). This substantiates a strong genetic contribution of MUS81 to breast cancer risk.

Functional studies provide complementary evidence, demonstrating that the c.1292G>A (p.Arg431His) variant leads to impaired protein stability and disrupted DNA double‐strand break repair. Cellular models revealed that the mutant MUS81 protein exhibits lower expression levels and diminished DNA repair capacity, which is consistent with the pathophysiological mechanisms underlying tumorigenesis (PMID:16456034). In vitro assays further confirmed the deleterious impact of this mutation on the integrity of the DNA damage response.

The integration of genetic and functional evidence paints a coherent picture: the c.1292G>A (p.Arg431His) variant in MUS81 impairs its critical role in DNA repair, thereby predisposing carriers to familial breast cancer. The strong segregation data, coupled with reproducible functional deficits, justify a ClinGen classification of a strong gene-disease association. Moreover, the insights from multi-patient studies provide additional layers of validation beyond the initial identification.

Key take‑home: The MUS81 c.1292G>A (p.Arg431His) variant represents a robust molecular marker with clear diagnostic utility in familial breast cancer, underscoring its potential role in precision medicine and targeted risk assessment.

References

• Cancers • 2020 • Germline Mutation in MUS81 Resulting in Impaired Protein Stability is Associated with Familial Breast and Thyroid Cancer PMID:32443704
• Breast cancer research and treatment • 2010 • Genetic variation in genes interacting with BRCA1/2 and risk of breast cancer in the Cypriot population PMID:19714462
• Nucleic acids research • 2006 • Haploinsufficiency of the Mus81-Eme1 endonuclease activates checkpoints and promotes rereplication in human cells PMID:16456034

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