Submissions for variant NM_000051.4(ATM):c.134G>A (p.Arg45Gln)

gnomAD frequency: 0.00001  dbSNP: rs762382111

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168047	SCV000218700	uncertain significance	Ataxia-telangiectasia syndrome	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 45 of the ATM protein (p.Arg45Gln). This variant is present in population databases (rs762382111, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 188157). 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.
Ambry Genetics	RCV000217445	SCV000276184	likely benign	Hereditary cancer-predisposing syndrome	2024-03-04	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.
GeneDx	RCV000235357	SCV000293679	uncertain significance	not provided	2020-01-27	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals diagnosed with breast cancer (Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823)
Color Diagnostics, LLC DBA Color Health	RCV000217445	SCV000913527	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 45 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. This variant has been reported in individuals affected with breast cancer and in unaffected individuals (PMID: 30287823). This variant has been identified in 2/251116 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.
Baylor Genetics	RCV003468822	SCV004210050	uncertain significance	Familial cancer of breast	2023-08-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586586	SCV005077257	uncertain significance	not specified	2024-04-18	criteria provided, single submitter	clinical testing	Variant summary: ATM c.134G>A (p.Arg45Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251116 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.134G>A has been reported in the literature in individuals affected with Breast Cancer and biliary tract cancer (Momozawa_2018, Okawa_2023), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30287823, 36243179). ClinVar contains an entry for this variant (Variation ID: 188157). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000168047	SCV001461807	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing