Submissions for variant NM_000051.4(ATM):c.4082A>G (p.Gln1361Arg)

gnomAD frequency: 0.00029  dbSNP: rs141921797

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164614	SCV000215277	likely benign	Hereditary cancer-predisposing syndrome	2022-11-22	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	RCV000167992	SCV000218642	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1361 of the ATM protein (p.Gln1361Arg). This variant is present in population databases (rs141921797, gnomAD 0.06%). This missense change has been observed in individual(s) with colon cancer or melanoma (PMID: 29684080, 34262154). ClinVar contains an entry for this variant (Variation ID: 185234). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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	RCV000479421	SCV000564637	uncertain significance	not provided	2024-11-21	criteria provided, single submitter	clinical testing	Observed in individuals with melanoma, prostate, colorectal, breast, and renal cancer (PMID: 29684080, 34262154, 35264596, 36898365, 31206626); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23555315, 29684080, 31871109, 34262154, 35264596, 36898365, 39324485, 31206626)
Color Diagnostics, LLC DBA Color Health	RCV000164614	SCV000682183	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 1361 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 an individual affected with melanoma (PMID: 34262154) and five carriers in a breast cancer case-control study, however the cancer status of the carriers were not specified (PMID: 31871109). This variant also has been reported in 9 individuals age 70 years or older without cancer (FLOSSIES; https://whi.color.com/variant/11-108158415-A-G). This variant has been identified in 17/280106 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.
Mendelics	RCV000167992	SCV000838533	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780899	SCV000918535	uncertain significance	not specified	2024-07-18	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4082A>G (p.Gln1361Arg) 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 4.8e-05 in 248700 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (4.8e-05 vs 0.001), allowing no conclusion about variant significance In addition, this variant has also been reported in 4/7325 European American and 5/2559 African American (i.e. with an allele frequency of 0.000977) women who were older than age 70 and cancer free (in the FLOSSIES database). The variant, c.4082A>G, has also been reported in the literature in cohorts of individuals affected with various tumor phenotypes, but without providing information on the associated phenotypes (examples: Haiman_2013, Yehia_2018, Adedokun_2020 and Dalmasso_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. The following publications have been ascertained in the context of this evaluation (PMID: 23555315, 29684080, 31871109, 34262154). ClinVar contains an entry for this variant (Variation ID: 185234). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479421	SCV001469350	likely benign	not provided	2023-06-21	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000479421	SCV001474796	uncertain significance	not provided	2019-12-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000780899	SCV002071339	uncertain significance	not specified	2019-10-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003153441	SCV003843110	uncertain significance	Familial cancer of breast	2022-10-13	criteria provided, single submitter	clinical testing	The ATM c.4082A>G (p.Gln1361Arg) missense change has a maximum subpopulation frequency of 0.060% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant was reported in five individuals in a study of breast cancer, however it was not specified if the variant was found in cases or controls (PMID: 31871109). This variant is present in nine individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003153441	SCV003936024	uncertain significance	Familial cancer of breast	2023-06-06	criteria provided, single submitter	clinical testing	A variant of uncertain significance was detected in the ATM gene. This sequence change replaces glutamine with arginine at codon 1361 of the ATM protein (p.Gln1361Arg). This variant is present in population databases (rs141921797, ExAC 0.07%). This variant has been observed in individual(s) with breast cancer (PMID: 23555315). ClinVar contains an entry for this variant (Variation ID: 185234). In-silico predictions show benign computational verdict based on 9 benign predictions from PolyPhen, BayesDel_addAF, DEOGEN2, EIGEN, LIST-S2, MVP, MutationTaster, PrimateAI and SIFT vs 4 pathogenic predictions from DANN, FATHMM-MKL, M-CAP and MutationAssessor and the position is not highly conserved. Therefore, it has been classified as a Variant of Uncertain Significance. Heterozygous pathogenic/likely pathogenic mutations in ATM gene cause breast cancer susceptibility (OMIM#114480).
Myriad Genetics, Inc.	RCV003153441	SCV005082108	likely benign	Familial cancer of breast	2024-05-16	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].
Natera, Inc.	RCV000167992	SCV001458200	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739522	SCV005366319	uncertain significance	ATM-related disorder	2024-08-08	no assertion criteria provided	clinical testing	The ATM c.4082A>G variant is predicted to result in the amino acid substitution p.Gln1361Arg. This variant was reported in several individuals with breast cancer (Table 5, Adedokun et al. 2020. PubMed ID: 31871109; Supp. Table 3, Guindalini et al. 2022. PubMed ID: 35264596; Table 3, Weitzel et al. 2019. PubMed ID: 31206626), in an individual with sporadic melanoma (Table S2, Dalmasso et al. 2021. PubMed ID: 34262154), and in an individual with Cowden syndrome (Table S9, Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD and is interpreted as a variant of uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185234/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.