Submissions for variant NM_000051.4(ATM):c.5825C>T (p.Ala1942Val)

gnomAD frequency: 0.00001  dbSNP: rs730881394

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159768	SCV000209789	likely pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25754356, 24090759, 22649200, 29641532, 34602955, 26896183, 33471991, 34262154)
Ambry Genetics	RCV000218056	SCV000274727	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-30	criteria provided, single submitter	clinical testing	The p.A1942V variant (also known as c.5825C>T), located in coding exon 38 of the ATM gene, results from a C to T substitution at nucleotide position 5825. The alanine at codon 1942 is replaced by valine, an amino acid with similar properties. This alteration has been detected in conjunction with the ATM mutation, c.7638_7646delTAGAATTTC, in two siblings with ataxia-telangiectasia (A-T) (Carney EF et al. J Immunol. 2012 Jul;189:261-8). Functional assays performed on their cells showed a high level of chromosomal radiosensitivity and absence of ATM kinase activity (Carney EF et al. J Immunol. 2012 Jul;189:261-8). The ATM p.A1942V variant has also been reported in conjunction with the ATM mutation, c.1898+2T>G, in a second individual with A-T (Davis MY et al. J. Neurol. Sci. 2013 Dec;335:134-8). In another study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463126	SCV000547006	pathogenic	Ataxia-telangiectasia syndrome	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1942 of the ATM protein (p.Ala1942Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia telangiectasia (A-T) (PMID: 22649200, 24090759; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 181999). 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 expected to disrupt ATM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATM function (PMID: 22649200). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000218056	SCV000913974	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1942 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported in three individuals affected with classic ataxia telangiectasia in compound heterozygosity with a known pathogenic variant (PMID: 22649200, 34602955). Cells from two of these patients showed significantly reduced levels of ATM protein (5% of wild type) and undetectable ATM kinase activity (PMID: 22649200). This variant has also been reported in compound heterozygosity with a pathogenic splice variant in an individual affected with a mild form of ataxia telangiectasia, who died at age 48 with pancreatic adenocarcinoma (PMID: 24090759). This variant has been identified in 1/251070 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Baylor Genetics	RCV003462077	SCV004207081	likely pathogenic	Familial cancer of breast	2024-03-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000159768	SCV004227578	likely pathogenic	not provided	2023-04-24	criteria provided, single submitter	clinical testing	PM2_supporting, PM3_very_strong
Myriad Genetics, Inc.	RCV003462077	SCV004931110	likely pathogenic	Familial cancer of breast	2024-01-26	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26896183, 22649200, 24090759, 34602955]. Functional studies indicate this variant impacts protein function [PMID: 26896183, 22649200, 24090759].
Counsyl	RCV000463126	SCV000798043	uncertain significance	Ataxia-telangiectasia syndrome	2018-02-20	flagged submission	clinical testing