ClinVar Miner

Submissions for variant NM_005591.3(MRE11):c.913C>T (p.Arg305Trp) (rs372000848)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212563 SCV000884127 uncertain significance not provided 2018-01-17 criteria provided, single submitter clinical testing The p.Arg305Trp variant has been reported in a heterozygous form in one individual with ovarian cancer (Heikkinen 2003). This variant (rs372000848) is listed in the Genome Aggregation Database (gnomAD) with allele frequency of 0.009 percent in non-Finnish European populations (identified on 11 out of 126,314) and has been reported to the ClinVar database (Variation ID: 127989). Arginine at codon 305 is highly conserved considering 13 species, up to Baker’s yeast (Alamut v2.10), and computational analyses support a deleterious impact on the protein structure and function (PolyPhen2: possibly damaging, SIFT: damaging, and Mutation Taster: disease causing). Altogether, the clinical significance of p.Arg305Trp variant cannot be determined with certainty.
Ambry Genetics RCV000115925 SCV000187182 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000212563 SCV000149834 likely pathogenic not provided 2014-01-08 criteria provided, single submitter clinical testing MRE11A has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted MRE11A c.913C>T at the cDNA level, p.Arg305Trp (R305W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). MRE11A Arg305Trp was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. This variant is a non-conservative substitution in which a positive polar amino acid is replaced with a neutral non-polar one, altering a position that is fully conserved throughout evolution and is located in the PDE motif V (Heikkinen 2003). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. Mutations in the MRE11A (also known as MRE11) gene have recently been associated with breast and ovarian cancer risk (Bartkova 2008, Heikkinen 2003, Walsh 2011). Heikkinen et al. (2003) screened women diagnosed with breast or ovarian cancer from 151 Finnish breast and/or ovarian cancer families for mutations in the MRE11A gene. In this series, one likely pathogenic variant was identified in a woman diagnosed with ovarian cancer at age 37 and a reported family history of cervical and uterine cancers. This MRE11A mutation was absent from 1000 controls. The authors noted that MRE11A Arg305Trp is located at the end of the functional domain, where it may be involved in causing structural instability leading to an increased susceptibility to cancer. Thus, Heikkinen et al. consider MRE11A Arg305Trp to be a likely pathogenic variant. Bartkova et al. (2008) screened 1000 breast tumor samples for reduced expression of the protein products of the MRE11A, RAD50, and NBS1 genes. Tumors from 8 patients showed reduced or no expression of these proteins, and two germline MRE11A mutations were identified in this group. Walsh et al. (2011) also identified a MRE11A mutation in 1/360 patients with ovarian cancer, peritoneal cancer, or fallopian tube cancer unselected for family history. Two mutations (one in each copy of the gene) in the MRE11A gene cause a rare ataxia telangiectasia-like disorder (A-TLD). When two individuals with known pathogenic MRE11A mutations have children, the risk of A-TLD is 25% with each pregnancy.
Invitae RCV000627767 SCV000260086 uncertain significance Ataxia-telangiectasia-like disorder 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 305 of the MRE11 protein (p.Arg305Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs372000848, ExAC 0.02%). This variant has been reported in an individual affected with ovarian cancer (PMID: 14684699). ClinVar contains an entry for this variant (Variation ID: 127989). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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