Submissions for variant NM_000051.4(ATM):c.3802G>A (p.Val1268Met)

gnomAD frequency: 0.00001  dbSNP: rs863224564

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196544	SCV000254091	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1268 of the ATM protein (p.Val1268Met). This variant is present in population databases (no rsID available, 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: 216204). 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. 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.
Ambry Genetics	RCV000215921	SCV000276086	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-03	criteria provided, single submitter	clinical testing	The p.V1268M variant (also known as c.3802G>A), located in coding exon 25 of the ATM gene, results from a G to A substitution at nucleotide position 3802. The valine at codon 1268 is replaced by methionine, 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.
GeneDx	RCV000483314	SCV000568179	uncertain significance	not provided	2019-07-17	criteria provided, single submitter	clinical testing	Not observed at a significant frequency 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
Counsyl	RCV000196544	SCV000799202	uncertain significance	Ataxia-telangiectasia syndrome	2018-04-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000215921	SCV000913930	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-22	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1268 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 1/251174 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.
Genetic Services Laboratory, University of Chicago	RCV001818482	SCV002064615	uncertain significance	not specified	2019-07-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468900	SCV004210277	uncertain significance	Familial cancer of breast	2023-12-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000196544	SCV002081415	uncertain significance	Ataxia-telangiectasia syndrome	2020-11-09	no assertion criteria provided	clinical testing