Submissions for variant NM_000051.4(ATM):c.2194A>G (p.Met732Val)

dbSNP: rs1415360560

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799669	SCV000939343	uncertain significance	Ataxia-telangiectasia syndrome	2022-08-06	criteria provided, single submitter	clinical testing	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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. ClinVar contains an entry for this variant (Variation ID: 645564). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 732 of the ATM protein (p.Met732Val).
Color Diagnostics, LLC DBA Color Health	RCV001189760	SCV001357119	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001662827	SCV001874201	uncertain significance	not provided	2021-07-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in breast cancer cases but also in unaffected controls (Momozawa 2018); This variant is associated with the following publications: (PMID: 27535533, 30287823)
Ambry Genetics	RCV001189760	SCV002728654	likely benign	Hereditary cancer-predisposing syndrome	2020-03-05	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003230594	SCV003926650	uncertain significance	Familial cancer of breast	2023-05-30	criteria provided, single submitter	clinical testing	a variant of uncertain significance in the ATM gene (c.2194A>G). This sequence change replaces methionine with valine at codon 732 of the ATM protein (p.Met732Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals with ATMrelated disease. In silico analysis supports that this missense variant does not alter protein structure/function;. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. Pathogenic and likely pathogenic mutations in the ATM gene are associated with increased risk of breast cancer.
Breakthrough Genomics, Breakthrough Genomics	RCV001662827	SCV005191424	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000799669	SCV002077154	uncertain significance	Ataxia-telangiectasia syndrome	2021-01-22	no assertion criteria provided	clinical testing