ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7957A>G (p.Ile2653Val)

gnomAD frequency: 0.00001  dbSNP: rs747448699
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000470182 SCV000547127 uncertain significance Ataxia-telangiectasia syndrome 2022-06-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2653 of the ATM protein (p.Ile2653Val). This variant is present in population databases (rs747448699, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 407719). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Color Diagnostics, LLC DBA Color Health RCV001523871 SCV001733573 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-10 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 2653 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251282 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.
Ambry Genetics RCV001523871 SCV002677446 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-31 criteria provided, single submitter clinical testing The p.I2653V variant (also known as c.7957A>G), located in coding exon 53 of the ATM gene, results from an A to G substitution at nucleotide position 7957. The isoleucine at codon 2653 is replaced by valine, an amino acid with highly similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is highly 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.
Natera, Inc. RCV000470182 SCV002076033 uncertain significance Ataxia-telangiectasia syndrome 2020-07-17 no assertion criteria provided clinical testing

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