rs863224463
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000051.4(ATM):c.7985T>A(p.Val2662Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2662I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7985T>A | p.Val2662Asp | missense_variant | 54/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7985T>A | p.Val2662Asp | missense_variant | 54/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459104Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 725998
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 22, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2022 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 14, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 03, 2021 | 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2020 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 08, 2021 | 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. - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 08, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 26, 2024 | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22071889, 23142947, 23322442, 34298181]. Functional studies indicate this variant impacts protein function [PMID: 22071889]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at