Submissions for variant NM_000051.4(ATM):c.4802G>A (p.Ser1601Asn)

gnomAD frequency: 0.00001  dbSNP: rs587782506

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131649	SCV000186676	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.
Invitae	RCV000205840	SCV000260967	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000236820	SCV000292997	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer or leukemia, and also in unaffected control subjects (Paglia et al., 2010; Skowronska et al., 2012; Decker et al., 2017; Dorling et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19404735, 21933854, 11443540, 28779002, 33280026, 33471991)
Mendelics	RCV000205840	SCV000838548	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131649	SCV000910699	likely benign	Hereditary cancer-predisposing syndrome	2015-04-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779764	SCV000916546	uncertain significance	not specified	2022-09-04	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4802G>A (p.Ser1601Asn) 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 3.2e-05 in 251834 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4802G>A has been reported in the literature in individuals with a variety of ATM-related cancers such as BRCA1/2-negative breast cancer, 11q deletion Chronic Lymphocytic Leukemia (CLL) (example, Pagila_2010, Skowronska_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia/Breast/ATM-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories and the Spanish ATM Cancer Susceptibility Variant Interpretation Working Group have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (VUS, n=4; likely benign, n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000205840	SCV001737198	likely benign	Ataxia-telangiectasia syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000131649	SCV001911462	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.4802G>A (p.Ser1601Asn) variant has an allele frequency of 0.000029 (0.003%, 7/236,740 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.000058 (0.006%, 2/34,254 alleles) in the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. Also, this missense variant does not alter the protein function / structure on the in-silico prediction reports of REVEL and Vest4 (BP4). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BP4 (PMID: 33280026).
Sema4, Sema4	RCV000131649	SCV002535399	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-01	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004551264	SCV004118011	uncertain significance	ATM-related disorder	2023-01-27	criteria provided, single submitter	clinical testing	The ATM c.4802G>A variant is predicted to result in the amino acid substitution p.Ser1601Asn. This variant has been reported in individuals with leukemia, polyposis, breast and ovarian cancer (Paglia et al. 2009. PubMed ID: 19404735; Skowronska et al. 2011. PubMed ID: 21933854. Table S1; Decker et al. 2017. PubMed ID: 28779002. Table S5; Feliubadaló et al. 2021. PubMed ID: 33280026. Table S3 and S4). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108165679-G-A). In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/142501/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236820	SCV004221109	uncertain significance	not provided	2023-03-31	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000028 (7/251276 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28779002 (2017), 19404735 (2010)) and ovarian cancer (PMID: 33280026 (2021)) as well as an individual with multiple colorectal adenomas (PMID: 33280026 (2021)) and chronic lymphocytic leukemia (CLL) (PMID: 21933854 (2011)). In a large-scale breast cancer association study, this variant was observed in breast cancer cases as well as unaffected control individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). 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.
Athena Diagnostics	RCV000236820	SCV004229250	uncertain significance	not provided	2023-03-31	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 higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging.