Submissions for variant NM_000051.4(ATM):c.6226A>G (p.Ile2076Val)

gnomAD frequency: 0.00001  dbSNP: rs755973863

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217659	SCV000278591	likely benign	Hereditary cancer-predisposing syndrome	2024-07-17	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	RCV000456769	SCV000547048	uncertain significance	Ataxia-telangiectasia syndrome	2024-08-22	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 2076 of the ATM protein (p.Ile2076Val). This variant is present in population databases (rs755973863, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer, colorectal cancer, and/or ovarian cancer (PMID: 25186627, 28135145, 34299313). ClinVar contains an entry for this variant (Variation ID: 234090). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine 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	RCV000456769	SCV000800429	uncertain significance	Ataxia-telangiectasia syndrome	2018-06-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000217659	SCV000903405	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 2076 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 and colorectal cancer (PMID: 25186627, 28135145, 34299313). This variant has been identified in 3/251394 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.
MGZ Medical Genetics Center	RCV002288898	SCV002579336	uncertain significance	Familial cancer of breast	2022-05-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494598	SCV002775973	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV003441803	SCV004168991	uncertain significance	not provided	2023-10-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23532176, 28135145, 16832357, 34299313)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488480	SCV004241428	uncertain significance	not specified	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6226A>G (p.Ile2076Val) results in a conservative amino acid change located in the PIK-related kinase (IPR014009) of 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 1.2e-05 in 251394 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6226A>G has been reported in the literature in individuals taking multiple-gene panel testing for Colorectal Cancer or unspecified contion involving DNA repair pathways, without strong evidence for causality (example, Yurgelun_2017, Guglielmi_2021). In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 1/60466 cases, not in 53461 controls (Dorling_2021 through LOVD).These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. 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: 33471991, 34299313, 28135145). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003441803	SCV005625158	uncertain significance	not provided	2024-09-21	criteria provided, single submitter	clinical testing	The ATM c.6226A>G (p.Ile2076Val) variant has been reported in the published literature in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 38136308 (2023), 34299313 (2021), 33471991 (2021), 25186627 (2015), 16832357 (2006), see also LOVD (http://databases.lovd.nl/shared)), and in an individual with colorectal cancer (PMID: 28135145 (2017)). The frequency of this variant in the general population, 0.000026 (3/113712 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.
Natera, Inc.	RCV000456769	SCV001457409	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739622	SCV005367052	uncertain significance	ATM-related disorder	2024-06-23	no assertion criteria provided	clinical testing	The ATM c.6226A>G variant is predicted to result in the amino acid substitution p.Ile2076Val. This variant was reported in individuals with colorectal cancer or breast cancer (Yurgelun et al. 2017. PubMed ID: 28135145; Tung N et al. 2014. PubMed ID: 25186627; Guglielmi C et al. 2021. PubMed ID: 34299313). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as a variant of uncertain significance by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/234090/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.