rs754395517
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000051.4(ATM):c.7522G>A(p.Gly2508Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,532 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G2508G) has been classified as Likely benign.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7522G>A | p.Gly2508Arg | missense_variant | 51/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7522G>A | p.Gly2508Arg | missense_variant | 51/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151650Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250694Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135578
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1459882Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 726238
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151650Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74034
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2508 of the ATM protein (p.Gly2508Arg). This variant is present in population databases (rs754395517, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome and/or prostate cancer (PMID: 25980754, 33436325). ClinVar contains an entry for this variant (Variation ID: 187265). 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 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 21, 2020 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 11, 2022 | This missense variant replaces glycine with arginine at codon 2508 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), an individual affected with prostate cancer (PMID: 33436325), and an individual affected with colorectal cancer (PMID: 34271781). In a large international case-control study, this variant was reported in 11/60466 breast cancer cases and 4/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 6/281930 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 26, 2022 | The p.G2508R variant (also known as c.7522G>A), located in coding exon 50 of the ATM gene, results from a G to A substitution at nucleotide position 7522. The glycine at codon 2508 is replaced by arginine, an amino acid with dissimilar properties. This variant was 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 amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with prostate, colorectal, or other cancers (Lu et al., 2015; Yurgelun et al., 2015; Duzkale et al., 2021; Karlsson et al., 2021); This variant is associated with the following publications: (PMID: 25980754, 26689913, 26757417, 34271781, 23532176, 33436325) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | ATM: BP4 - |
ATM-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 01, 2023 | The ATM c.7522G>A variant is predicted to result in the amino acid substitution p.Gly2508Arg. This variant has been identified in an individual undergoing Lynch syndrome-testing (Yurgelun et al. 2015. PubMed ID: 25980754, Table S2), an individual with glioblastoma multiforme (Lu et al. 2015. PubMed ID: 26689913, Table S12), and an individual with prostate cancer (Karlsson et al. 2021. PubMed ID: 33436325, Table S4). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108202177-G-A) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187265/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 26, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at