ClinVar Miner

Submissions for variant NM_005591.4(MRE11):c.2042C>T (p.Ser681Leu)

gnomAD frequency: 0.00002  dbSNP: rs587782166
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130759 SCV000185650 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-27 criteria provided, single submitter clinical testing The p.S681L variant (also known as c.2042C>T), located in coding exon 18 of the MRE11A gene, results from a C to T substitution at nucleotide position 2042. The serine at codon 681 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in a cohort of 122 patients who underwent multi-gene panel testing for hereditary cancer after having previously tested negative for mutations in BRCA1 and BRCA2 (Yadav S et al. Fam Cancer, 2017 07;16:319-328). This variant was reported in 1/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000410737 SCV000489078 uncertain significance Ataxia-telangiectasia-like disorder 1 2016-08-16 criteria provided, single submitter clinical testing
Invitae RCV001034669 SCV000547412 uncertain significance Ataxia-telangiectasia-like disorder 2022-08-16 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 681 of the MRE11 protein (p.Ser681Leu). This variant is present in population databases (rs587782166, gnomAD 0.002%). This missense change has been observed in individual(s) with a personal or family history of breast and ovarian cancer (PMID: 27878467). ClinVar contains an entry for this variant (Variation ID: 141995). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV001753515 SCV001996227 uncertain significance not provided 2019-09-27 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in at least one individual with a personal and/or family history of breast cancer; however, no additional information was provided (Yadav et al., 2017); This variant is associated with the following publications: (PMID: 27878467)
Fulgent Genetics, Fulgent Genetics RCV000410737 SCV002775997 uncertain significance Ataxia-telangiectasia-like disorder 1 2021-11-10 criteria provided, single submitter clinical testing

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