rs1805362 — MRE11

MRE11 Met698Val — A Benign Population Variant in a Gene Essential for Meiotic DNA Repair

MRE11 (double strand break repair nuclease) is the enzymatic core of the MRN complex¹¹ MRN complex
The MRE11-RAD50-NBS1 heterocomplex acts as the cell's first responder to DNA double-strand breaks — the most lethal form of DNA damage. It detects breaks, tethers broken ends, activates the ATM kinase checkpoint, and initiates the DNA end resection required for homologous recombination repair, the three-protein assembly that acts as the cell's primary sensor and first responder to DNA double-strand breaks (DSBs)²² DNA double-strand breaks (DSBs)
DSBs — complete severances of both DNA strands — are caused by ionizing radiation, replication fork collapse, reactive oxygen species, and are deliberately induced during meiosis to initiate crossover formation. MRE11 contributes two distinct nuclease activities — a 3′–5′ exonuclease and a strand-specific endonuclease — that cleave DNA ends to create the single-stranded overhangs needed for homologous recombination (HR) repair to begin. The complex also activates the ATM checkpoint kinase and maintains telomere length.

What makes MRE11 especially relevant to gamete biology is its indispensable role in meiosis. During egg and sperm formation, cells deliberately induce hundreds of DSBs to trigger recombination between homologous chromosomes — the process that generates genetic diversity and ensures chromosomes segregate correctly. Kim et al. (2025, Nat Commun)³³ Kim et al. (2025, Nat Commun)
Kim S et al. Mouse MRE11-RAD50-NBS1 is needed to start and extend meiotic DNA end resection. Nat Commun, 2025 showed that MRN is required not only to initiate but to extend meiotic DNA end resection, and that MRE11 deletion in mouse testis causes catastrophic spermatogenic failure. Cherry et al. (2007, Curr Biol)⁴⁴ Cherry et al. (2007, Curr Biol)
Cherry SM et al. The Mre11 complex influences DNA repair, synapsis, and crossing over in murine meiosis. Curr Biol, 2007 showed that MRE11 complex hypomorphs (partial loss-of-function mutants) develop incomplete chromosome synapsis and altered crossover frequency and placement in a sex-dimorphic pattern — males with more recombination, females with less.

The rs1805362 variant (T>C on the plus strand, p.Met698Val in the coding sequence) substitutes methionine with valine at position 698 of the MRE11 protein. Methionine and valine are both nonpolar aliphatic residues; the substitution is chemically conservative. Multiple ClinVar submitters classify this variant as benign⁵⁵ benign
ClinVar VCV000129622: 11/15 submissions classify as Benign, including GeneDx, LabCorp, Athena, Illumina, Ambry Genetics. The variant is 300-fold more common in African populations than expected for a pathogenic allele based on conservative amino acid change, location outside known functional domains, and an ~17–22× higher frequency in African populations than in Europeans — a pattern inconsistent with pathogenicity.

The Mechanism

MRE11 is encoded on chromosome 11 at position 94,420,160 (GRCh38). The gene is transcribed from the minus (complement) strand, so the plus-strand T (reference) corresponds to coding adenine (Met698), and the plus-strand C (alternate) corresponds to coding guanine (Val698). Position 698 lies outside the characterized N-terminal nuclease domain (residues ~1–420)⁶⁶ N-terminal nuclease domain (residues ~1–420)
The catalytic core of MRE11; contains the phosphoesterase motifs responsible for exonuclease and endonuclease activity; most ATLD-causing mutations cluster here and outside the RAD50-binding regions. Five in-silico tools (ClinVar submitter evidence) predict a benign effect; the position is described as "poorly conserved" across vertebrates. In contrast to ATLD-causing MRE11 mutations — which abolish nuclease activity or destabilize the complex and cause ataxia-telangiectasia-like disorder — Val698 is not expected to significantly alter MRE11's nuclease activities or its interaction with RAD50 and NBS1.

The Evidence

A 2024 meta-analysis of 53 studies by Stastna et al.⁷⁷ Stastna et al.
Stastna B et al. Germline pathogenic variants in the MRE11, RAD50, and NBN (MRN) genes in cancer predisposition. Int J Cancer, 2024 found that carriers of germline pathogenic variants in MRE11 had an odds ratio of 3.00 (95% CI 1.27–6.08) for ovarian cancer in a secondary burden analysis — but no elevated breast cancer risk (OR 0.87). This analysis covers high-impact loss-of-function and likely-pathogenic MRE11 variants, not the benign Met698Val polymorphism. It provides biological context: when MRE11 function is genuinely compromised, the ovarian germline is particularly vulnerable, consistent with the known dependence of oocyte maintenance on HR-repair capacity demonstrated by Titus et al.⁸⁸ Titus et al.
Titus S et al. Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. Sci Transl Med, 2013 for BRCA1-linked DSB repair. The specific Met698Val variant has not been associated with elevated cancer or fertility risk in published literature; no study has examined its effect on meiotic crossover quality or gamete aneuploidy rates.

No published pharmacogenomics data exists for this variant.

Practical Actions

For carriers of the TC genotype: the variant is classified benign by multiple expert laboratories; no specific clinical action is indicated by this genotype alone. The MRE11 context — a gene critical for meiotic crossover resolution — motivates awareness when building a complete DNA repair gene profile in the reproductive context, particularly for individuals pursuing IVF, where cumulative DNA repair gene variant burden is an emerging factor in embryo quality assessment.

For individuals with personal or family history of ovarian cancer: the pathogenic MRE11 variant data (OR 3.00 for ovarian cancer) applies to loss-of-function variants, not to Met698Val. However, a complete MRE11 sequencing result (including all variants) should be shared with a genetic counselor in that context.

Interactions

EXO1 rs72755295: EXO1 (exonuclease 1) is recruited downstream of MRN to extend DNA end resection after MRN initiates it. The EXO1 rs72755295 G allele increases EXO1 expression and is associated with earlier menopause — suggesting excessive exonuclease activity depletes the ovarian follicle pool. The MRN-EXO1 handoff is a mechanistic bottleneck in meiotic resection; no study has examined the combined effect of MRE11 variants and the EXO1 rs72755295 allele.

MLH1 rs1799977: MLH1 (mutL homolog 1) marks ~90% of obligate meiotic crossover sites and operates downstream of MRN-initiated resection. An individual carrying both MRE11 Met698Val and MLH1 Ile219Val would have two benign-classified variants at distinct steps of the meiotic crossover pathway — upstream initiation (MRE11) and downstream crossover designation (MLH1). While each is benign individually, the combined effect on meiotic crossover quality has not been studied.