ClinVar Miner

Submissions for variant NM_005591.3(MRE11):c.2076T>A (p.Asp692Glu) (rs778093337)

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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 RCV000163872 SCV000214459 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing The p.D692E variant (also known as c.2076T>A), located in coding exon 19 of the MRE11A gene, results from a T to A substitution at nucleotide position 2076. The aspartic acid at codon 692 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration was 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 amino acid position is highly 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.
Invitae RCV000524528 SCV000288940 uncertain significance Ataxia-telangiectasia-like disorder 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 692 of the MRE11 protein (p.Asp692Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs778093337, ExAC 0.002%). This variant has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 31159747, 27878467). ClinVar contains an entry for this variant (Variation ID: 184593). 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, 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.
GeneKor MSA RCV000163872 SCV000822032 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001110619 SCV001268080 uncertain significance Ataxia-telangiectasia-like disorder 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Baylor Genetics RCV001110619 SCV001520877 uncertain significance Ataxia-telangiectasia-like disorder 1 2019-11-26 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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