Submissions for variant NM_000051.4(ATM):c.2531G>A (p.Gly844Glu)

dbSNP: rs587781808

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130079	SCV000184906	likely benign	Hereditary cancer-predisposing syndrome	2019-05-04	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	RCV000211983	SCV000209708	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32383162, 31173963, 28779002, 29522266, 29206716)
Invitae	RCV000168121	SCV000218778	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 844 of the ATM protein (p.Gly844Glu). This variant is present in population databases (rs587781808, gnomAD 0.004%). This missense change has been observed in individual(s) with ATM-related cancers (PMID: 32383162). ClinVar contains an entry for this variant (Variation ID: 141514). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid 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.
Counsyl	RCV000168121	SCV000792870	uncertain significance	Ataxia-telangiectasia syndrome	2017-07-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130079	SCV000911592	likely benign	Hereditary cancer-predisposing syndrome	2017-04-07	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288634	SCV002579724	uncertain significance	Familial cancer of breast	2021-12-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226209	SCV003922905	uncertain significance	not specified	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2531G>A (p.Gly844Glu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251404 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2531G>A has been reported in the literature in individuals affected with breast cancer without strong evidnce for causality (example: Hilbers_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Prostate Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classifed the variant as VUS (n=4) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004551252	SCV004116787	uncertain significance	ATM-related disorder	2023-01-27	criteria provided, single submitter	clinical testing	The ATM c.2531G>A variant is predicted to result in the amino acid substitution p.Gly844Glu. This variant has been reported in individuals with breast cancer, an individual with epithelioid hemangioma, and a hepatic carcinoma specimen (Table 1, Subramaniam et al. 2018. PubMed ID: 29206716; Table S2, Hauke et al. 2018. PubMed ID: 29522266; Table S5, Decker et al. 2017. PubMed ID: 28779002; Table 3, Hilbers et al. 2020. PubMed ID: 32383162; Table 2, Howell et al. 2019. PubMed ID: 31173963). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108137962-G-A) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/141514/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000211983	SCV004133250	uncertain significance	not provided	2022-05-01	criteria provided, single submitter	clinical testing	ATM: PM2, BP4
Baylor Genetics	RCV002288634	SCV004209474	uncertain significance	Familial cancer of breast	2023-09-11	criteria provided, single submitter	clinical testing