Submissions for variant NM_000051.4(ATM):c.1379C>T (p.Thr460Met)

gnomAD frequency: 0.00002  dbSNP: rs587781841

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130139	SCV000184973	likely benign	Hereditary cancer-predisposing syndrome	2020-10-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466948	SCV000546849	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 460 of the ATM protein (p.Thr460Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic ductal adenocarcinoma (PMID: 32255556). ClinVar contains an entry for this variant (Variation ID: 141561). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000478287	SCV000565853	uncertain significance	not provided	2017-07-17	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.1379C>T at the cDNA level, p.Thr460Met (T460M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr460Met was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr460Met occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Thr460Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV000478287	SCV000805496	uncertain significance	not provided	2017-07-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130139	SCV000913545	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 460 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 performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. In a large international case-control study, this variant was reported in 0/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196781	SCV001367414	uncertain significance	Familial cancer of breast	2019-10-08	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,BP4.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004595932	SCV005089992	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000466948	SCV002095333	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-31	no assertion criteria provided	clinical testing