11-108353831-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_000051.4(ATM):c.8737G>T(p.Asp2913Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.8737G>T | p.Asp2913Tyr | missense_variant | Exon 60 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727220
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2
Variant summary: ATM c.8737G>T (p.Asp2913Tyr) results in a non-conservative amino acid change located in the ATM, catalytic domain (IPR044107) of 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 251460 control chromosomes (gnomAD). c.8737G>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (e.g. Micol_2011, Jacquemin_2012). The variant has also been reported in individuals affected with breast and prostate cancer (e.g. Lu_2019, Dorling_2021, Karlsson_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that the variant results in reduced protein expression, while it alters subcellular localization and cell cycle distribution and it impairs phosphorylation of target proteins such as H2AX, CHK2 and KAP1 (Jacquemin_2012, Fievet_2019). Three ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 2913 of the ATM protein (p.Asp2913Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ataxia-telangiectasia and/or prostate cancer (PMID: 21665257, 22071889, 33436325). ClinVar contains an entry for this variant (Variation ID: 230841). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATM protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ATM function (PMID: 22071889, 31050087). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.D2913Y variant (also known as c.8737G>T), located in coding exon 59 of the ATM gene, results from a G to T substitution at nucleotide position 8737. The aspartic acid at codon 2913 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with a clinical diagnosis of ataxia-telangiectasia in both homozygous and compound heterozygous states (Micol R et al. J. Allergy Clin. Immunol. 2011 Aug;128(2):382-9). Cell lines from an individual with ataxia telangiectasia who was heterozygous for this alteration along with a second alteration in ATM, exhibited decreased response to ionizing radiation, decreased ATM protein expression, and abnormal cellular localization (Jacquemin V et al. Eur. J. Hum. Genet. 2012 Mar;20(3):305-12). Additionally, this alteration has been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This variant was also reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 08;4:570-579). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. -
This missense variant replaces aspartic acid with tyrosine at codon 2913 of the ATM protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein function. Functional studies have shown that this variant results in reduced protein expression, abnormal sub-cellular localization, and disrupted phosphorylation activity (PMID: 22071889, 31050087). This variant has been reported in individuals affected with ataxia-telangiectasia in homozygosity and compound heterozygosity with a known pathogenic co-variant (PMID: 21665257, 31050087). In addition, this variant has been reported in individuals affected with breast cancer (PMID: 28779002, 30128536, 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -
ATM-related cancer predisposition Pathogenic:1
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Familial cancer of breast Pathogenic:1
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21665257, 25122203]. Functional studies indicate this variant impacts protein function [PMID: 22071889, 31050087]. 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