Submissions for variant NM_000051.4(ATM):c.1208C>T (p.Ser403Leu)

dbSNP: rs747563556

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000570080	SCV000660685	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	The p.S403L variant (also known as c.1208C>T), located in coding exon 8 of the ATM gene, results from a C to T substitution at nucleotide position 1208. The serine at codon 403 is replaced by leucine, an amino acid with dissimilar properties. In one study, this alteration was not detected in 7051 unselected breast cancer patients, but reported with a carrier frequency of 0.00018 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000570080	SCV000911721	uncertain significance	Hereditary cancer-predisposing syndrome	2019-01-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035293	SCV001198617	uncertain significance	Ataxia-telangiectasia syndrome	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 403 of the ATM protein (p.Ser403Leu). This variant is present in population databases (rs747563556, gnomAD 0.01%). 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: 479032). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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.
GeneDx	RCV001584368	SCV001818828	uncertain significance	not provided	2019-06-03	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; This variant is associated with the following publications: (PMID: 30287823)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701654	SCV005202728	uncertain significance	not specified	2024-07-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1208C>T (p.Ser403Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251198 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1208C>T in individuals affected with ATM-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 479032). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001035293	SCV002092790	uncertain significance	Ataxia-telangiectasia syndrome	2020-12-23	no assertion criteria provided	clinical testing