Submissions for variant NM_000051.4(ATM):c.398A>T (p.Asn133Ile)

dbSNP: rs730881330

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159666	SCV000209666	uncertain significance	not provided	2024-09-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense 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: 33471991)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543356	SCV000622464	likely benign	Ataxia-telangiectasia syndrome	2023-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001021590	SCV001183226	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-29	criteria provided, single submitter	clinical testing	The p.N133I variant (also known as c.398A>T), located in coding exon 4 of the ATM gene, results from an A to T substitution at nucleotide position 398. The asparagine at codon 133 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193630	SCV001362598	uncertain significance	not specified	2019-01-15	criteria provided, single submitter	clinical testing	Variant summary: ATM c.398A>T (p.Asn133Ile) results in a non-conservative amino acid change in the telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246066 control chromosomes (gnomAD). 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.398A>T in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001021590	SCV002051932	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 133 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. In a large international case-control study, this variant was reported in 0/60466 breast cancer cases and 1/53460 controls (PMID: 33471991). This variant has been identified in 1/251286 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.
Natera, Inc.	RCV000543356	SCV002090867	uncertain significance	Ataxia-telangiectasia syndrome	2021-09-25	no assertion criteria provided	clinical testing