ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7984G>A (p.Val2662Ile)

gnomAD frequency: 0.00001  dbSNP: rs1315805984
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000527553 SCV000622790 likely pathogenic Ataxia-telangiectasia syndrome 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2662 of the ATM protein (p.Val2662Ile). This variant is not present in population databases (gnomAD no frequency). 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: 453713). 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. This variant disrupts the p.Val2662 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22071889, 23142947, 23322442). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Counsyl RCV000527553 SCV000799401 uncertain significance Ataxia-telangiectasia syndrome 2018-04-17 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001180547 SCV001345499 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-26 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 2662 of the ATM protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
GeneDx RCV001597153 SCV001830763 uncertain significance not provided 2019-05-03 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23142947, 22071889, 23322442, 28492532)
Sema4, Sema4 RCV001180547 SCV002537800 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-17 criteria provided, single submitter curation
Ambry Genetics RCV001180547 SCV002681654 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-22 criteria provided, single submitter clinical testing The p.V2662I variant (also known as c.7984G>A), located in coding exon 53 of the ATM gene, results from a G to A substitution at nucleotide position 7984. The valine at codon 2662 is replaced by isoleucine, an amino acid with highly similar properties. 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.
Fulgent Genetics, Fulgent Genetics RCV005044788 SCV005680921 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2024-06-18 criteria provided, single submitter clinical testing

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