MRE11 – Breast Cancer

Heterozygous germline variants in MRE11 (HGNC:7230) have been implicated in moderate‐risk susceptibility to breast cancer (MRE11; breast cancer). A truncating allele, c.1090C>T (p.Arg364Ter), was identified in a BRCA-negative familial breast and endometrial cancer pedigree, resulting in loss of both the GAR domain and RAD50‐binding site and abolition of nuclease function (PMID:28559769). In a Chinese case-control study, the MRE11A rs2155209 SNP conferred an increased breast cancer risk (OR 1.87, 95% CI 1.23–2.86) (PMID:25566853). A large Breast Cancer Family Registry screening of 1,313 early-onset cases and 1,123 controls pooled rare truncating and key domain missense variants in MRN complex genes, including MRE11, and found an intermediate risk (OR 2.88, P = 0.0090) (PMID:24894818).

Inheritance is autosomal dominant with reduced penetrance. Segregation data are limited to a single family carrying the p.Arg364Ter variant, with at least two additional affected relatives segregating the allele. Functional studies support a loss-of-function mechanism: the p.Arg364Ter truncation abolishes critical domains for DNA double-strand break repair, while yeast and mammalian models demonstrate that disruption of Mre11 nuclease activity or complex assembly impairs DSB processing and checkpoint activation.

Conflicting evidence arises from the WECARE study, which found no significant association between MRE11A variants and contralateral breast cancer risk in 649 cases versus 1,284 controls (PMID:21898661). Integration of genetic and functional data supports a Moderate clinical validity for MRE11 in breast cancer predisposition, warranting inclusion in multigene panels for moderate‐risk assessment.

Key Take-home: Germline MRE11 variants confer moderate risk for breast cancer via a haploinsufficiency mechanism, supporting their use in clinical multigene testing.

References

• Breast care (Basel, Switzerland) • 2017 • Next-Generation Sequencing Reveals a Nonsense Mutation (p.Arg364Ter) in MRE11A Gene in an Indian Patient with Familial Breast Cancer. PMID:28559769
• Molecular genetics and genomics : MGG • 2015 • Evaluation of miRNA-binding-site SNPs of MRE11A, NBS1, RAD51 and RAD52 involved in HRR pathway genes and risk of breast cancer in China. PMID:25566853
• Breast cancer research : BCR • 2014 • Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study. PMID:24894818
• Human mutation • 2012 • Variants in activators and downstream targets of ATM, radiation exposure, and contralateral breast cancer risk in the WECARE study. PMID:21898661

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