Submissions for variant NM_000051.4(ATM):c.7985T>A (p.Val2662Asp)

dbSNP: rs863224463

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000200768	SCV000253747	pathogenic	Ataxia-telangiectasia syndrome	2022-12-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATM function (PMID: 22071889). 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. ClinVar contains an entry for this variant (Variation ID: 216025). This missense change has been observed in individuals with ataxia telangiectasia (PMID: 22071889, 23142947, 23322442). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2662 of the ATM protein (p.Val2662Asp).
Counsyl	RCV000200768	SCV000797315	likely pathogenic	Ataxia-telangiectasia syndrome	2018-01-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200768	SCV001737760	pathogenic	Ataxia-telangiectasia syndrome	2021-06-03	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7985T>A (p.Val2662Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251228 control chromosomes. c.7985T>A has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Jacquemin_2012, Landoure_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed that ATM-V2662D had decreased expression level, mislocalization to cytoplasm, and decreased phosphorylation of ATM target proteins (Jacquemin_2012, Fievet_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic/likely pathogenic n=2, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000200768	SCV002022366	pathogenic	Ataxia-telangiectasia syndrome	2019-05-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001176540	SCV002678061	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-29	criteria provided, single submitter	clinical testing	The p.V2662D pathogenic mutation (also known as c.7985T>A), located in coding exon 53 of the ATM gene, results from a T to A substitution at nucleotide position 7985. The valine at codon 2662 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration has been seen in the homozygous state in multiple individuals diagnosed with ataxia-telangiectasia, including three out of three affected siblings in one consanguineous family (Jacquemin V et al. Eur. J. Hum. Genet. 2012 Mar;20:305-12; Landouré G et al. J. Neurol. 2013 Jan;260:324-6; Jeddane L et al. Neuromolecular Med. 2013 Jun;15:288-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003468895	SCV004212097	pathogenic	Familial cancer of breast	2023-02-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001176540	SCV004361874	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-09-08	criteria provided, single submitter	clinical testing	This missense variant replaces valine with aspartic acid at codon 2662 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in the homozygous state in multiple individuals affected with ataxia telangiectasia (PMID: 22071889, 22109722, 23142947, 23322442, 27066513, 31050087). Cells derived from these individuals showed decreased nuclear ATM protein level and decreased phosphorylation of CHK2 and KAP1 (PMID: 22071889, 31050087). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.