Submissions for variant NM_000051.4(ATM):c.649A>G (p.Ile217Val)

gnomAD frequency: 0.00003  dbSNP: rs547045780

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217843	SCV000275746	likely benign	Hereditary cancer-predisposing syndrome	2024-04-04	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472458	SCV000546947	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 217 of the ATM protein (p.Ile217Val). This variant is present in population databases (rs547045780, gnomAD 0.006%). This missense change has been observed in individual(s) with prostate cancer, breast cancer (PMID: 29659569, 35451682). ClinVar contains an entry for this variant (Variation ID: 133639). 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.
GeneDx	RCV000657028	SCV000566770	uncertain significance	not provided	2023-05-26	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: 33471991, 31206626, 29659569, 24728327)
Color Diagnostics, LLC DBA Color Health	RCV000217843	SCV000687707	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 217 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. In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 4/282528 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.
Counsyl	RCV000472458	SCV000790108	uncertain significance	Ataxia-telangiectasia syndrome	2017-03-06	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000657028	SCV001475565	uncertain significance	not provided	2024-03-13	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools predict that this variant is not damaging.
Sema4, Sema4	RCV000217843	SCV002537711	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-18	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657028	SCV003799708	uncertain significance	not provided	2022-05-05	criteria provided, single submitter	clinical testing	The ATM c.649A>G; p.Ile217Val variant (rs547045780), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 133639). This variant is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 217 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.059). Due to limited information, the clinical significance of the p.Ile217Val variant is uncertain at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120164	SCV003929127	uncertain significance	not specified	2023-04-20	criteria provided, single submitter	clinical testing	Variant summary: ATM c.649A>G (p.Ile217Val) results in a 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 8e-06 in 251194 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.649A>G has been reported in the literature in individuals affected with prostate cancer or breat cancer (Paulo_2018, Dorling_2021). 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003467071	SCV004209560	uncertain significance	Familial cancer of breast	2023-08-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467071	SCV005085808	likely benign	Familial cancer of breast	2024-04-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Breakthrough Genomics, Breakthrough Genomics	RCV000657028	SCV005192267	uncertain significance	not provided		criteria provided, single submitter	not provided
Mendelics	RCV004700427	SCV005205576	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000217843	SCV005415554	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-12	criteria provided, single submitter	clinical testing	The variant is observed in one or more well-documented healthy adults. There is a small physicochemical difference between isoleucine and valine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene ATM has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 2.52. The gene ATM contains 167 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. For these reasons, this variant has been classified as Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657028	SCV005625993	uncertain significance	not provided	2023-10-03	criteria provided, single submitter	clinical testing	The ATM variant has been reported in the published literature in a reportedly healthy individual (PMID: 24728327 (2014)), as well as in two breast cancer cases in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000014 (4/282528 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
ITMI	RCV000120164	SCV000084306	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000472458	SCV002085297	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-19	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551181	SCV004742561	uncertain significance	ATM-related disorder	2024-06-03	no assertion criteria provided	clinical testing	The ATM c.649A>G variant is predicted to result in the amino acid substitution p.Ile217Val. This variant has been reported in an individual from an ancestrally diverse genome sequencing cohort (Table S1, Bodian et al. 2014. PubMed ID: 24728327). It has also been reported in individuals with a history of breast cancer (listed as g.chr11_108114832_A_G in Supplementary Table, Dorling et al. 2021. PubMed ID: 33471991), but has also been reported in control cohorts (Table S3, Weitzel et al. 2019. PubMed ID: 31206626). Multiple in silico prediction tools predict this variant to be tolerated (Table S2, Paulo et al. 2018. PubMed ID: 29659569). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/133639/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.