rs748634900
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000051.4(ATM):c.8293G>A(p.Gly2765Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,724 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. G2765D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.8293G>A | p.Gly2765Ser | missense_variant | 57/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.8293G>A | p.Gly2765Ser | missense_variant | 57/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251386Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135858
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461724Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727170
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2765 of the ATM protein (p.Gly2765Ser). This variant is present in population databases (rs748634900, gnomAD 0.002%). This missense change has been observed in individuals with ataxia-telangiectasia (PMID: 10534763, 19781682, 21792198). ClinVar contains an entry for this variant (Variation ID: 186351). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 19431188, 21792198). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 02, 2024 | Variant summary: ATM c.8293G>A (p.Gly2765Ser) 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 allele was found at a frequency of 7.9e-06 in 251598 control chromosomes (gnomAD). c.8293G>A has been reported in the literature in individuals affected Ataxia Telangectasia (A-T) as well as breast cancer patients, however segregation studies in a breast cancer family showed the variant to be absent in an affected grandmother, while the variant was present in two unaffected siblings (age at testing was not specified). This data indicate a lack of co-segregation of this variant with breast cancer in this family (Izatt_1999), although the effect of a limited penetrance, cannot be ruled out. Furthermore, a sample tested at our laboratory also carries another pathogenic BRCA2 c.5946delT. Among the cohort of patients clinically diagnosed with A-T, this variant was seen in compound heterozygosity with other possibly pathogenic variants. Well controlled functional studies have shown the variant to lead to loss of ATM Kinase activity, while retaining almost complete ATM protein expression (Barone_2009, Reiman_2011). The following publications have been ascertained in the context of this evaluation (PMID: 19431188, 21787400, 19781682, 10534763, 15928302, 21792198). ClinVar contains an entry for this variant (Variation ID: 186351). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Familial cancer of breast Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 01, 2024 | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21792198, 19431188, 37438524]. Functional studies indicate this variant impacts protein function [PMID: 21792198, 19431188]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 20, 2022 | This missense variant replaces glycine with serine at codon 2765 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). Functional studies have shown that this variant protein has no detectable kinase activity and leads to cell cycle checkpoint defect in cell-based assays (PMID: 19431188). This variant has been reported in the compound heterozygous state in individuals affected with ataxia telangiectasia (PMID: 21792198, 25040471). This variant has also been reported in individuals affected with breast cancer (PMID: 10534763, 19781682). This variant has been identified in 2/251386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 20, 2021 | The p.G2765S pathogenic mutation (also known as c.8293G>A), located in coding exon 56 of the ATM gene, results from a G to A substitution at nucleotide position 8293. The glycine at codon 2765 is replaced by serine, an amino acid with similar properties. This residue resides within the PI-3 kinase functional domain of the ATM protein, and this alteration was demonstrated to result in a protein product that lacks ATM kinase activity, is deficient at the G2/M checkpoint, and interferes with the phosphorylation activity of wild-type ATM (Izatt L et al.Genes Chromosomes Cancer. 1999 Dec; 26(4):286-94; Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30). This mutation has been reported in several patients with a clinical diagnosis of ataxia-telangiectasia, including a woman with ataxia-telangiectasia and breast cancer diagnosed under the age of 50 (Reiman A et al. Br. J. Cancer. 2011 Aug; 105(4):586-91; Taylor AM et al. Clin. Genet. 2014 Jul; Ambry Internal Data). This alteration was also observed in 1/4112 breast cancer patients and 0/2399 healthy controls (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct; 85(4):427-46). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at