Submissions for variant NM_005591.4(MRE11):c.2076T>A (p.Asp692Glu)

dbSNP: rs778093337

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163872	SCV000214459	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-07	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 BRCA1/2-negative patients who underwent multi-gene panel testing for hereditary cancer (Yadav S et al. Fam. Cancer. 2017 07;16:319-328). This alteration was also reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis G et al. BMC Cancer 2019 Jun;19(1):535). 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	2021-09-01	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 missense change has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 27878467, 31159747). 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. 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 Laboratory Services, 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].