ClinVar Miner

Submissions for variant NM_005591.4(MRE11):c.463C>T (p.Arg155Cys)

gnomAD frequency: 0.00001  dbSNP: rs587782512
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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 RCV000131662 SCV000186690 uncertain significance Hereditary cancer-predisposing syndrome 2022-06-29 criteria provided, single submitter clinical testing The p.R155C variant (also known as c.463C>T), located in coding exon 5 of the MRE11A gene, results from a C to T substitution at nucleotide position 463. The arginine at codon 155 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000700255 SCV000829003 uncertain significance Ataxia-telangiectasia-like disorder 2023-09-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 155 of the MRE11 protein (p.Arg155Cys). This variant is present in population databases (rs587782512, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with MRE11-related conditions. ClinVar contains an entry for this variant (Variation ID: 142512). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research RCV001030701 SCV001193623 uncertain significance Hereditary breast ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002509243 SCV002819483 uncertain significance not specified 2022-12-12 criteria provided, single submitter clinical testing Variant summary: MRE11 c.463C>T (p.Arg155Cys) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type (IPR004843) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250950 control chromosomes (gnomAD v2.1, exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.463C>T, has been reported in the literature in individuals affected with breast cancer (Young_2016) and stomach cancer (Schwartz_2022), however without providing evidence of causality. The variant has also been reported in 1 / 7325 European American women, who are older than age 70 and cancer free (FLOSSIES database). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 6/60466 cases, and in 1/53461 controls (Dorling_2021, reported through LOVD). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV003467181 SCV004193817 uncertain significance Ataxia-telangiectasia-like disorder 1 2023-08-10 criteria provided, single submitter clinical testing

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