Submissions for variant NM_000051.4(ATM):c.6543G>T (p.Glu2181Asp)

gnomAD frequency: 0.00056  dbSNP: rs138828590

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587205	SCV000149139	uncertain significance	not provided	2024-06-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history of breast cancer (PMID: 20305132, 26976419, 29684080, 31206626, 31871109, 33646313, 35039564, 35264596); This variant is associated with the following publications: (PMID: 30413523, 26976419, 26689913, 21787400, 25182519, 20305132, 23555315, 28652578, 32098697, 31871109, 33646313, 35039564, 30447919, 33606809, 29684080, 31206626, 35264596, 23532176, 35534704)
Ambry Genetics	RCV000115230	SCV000214314	likely benign	Hereditary cancer-predisposing syndrome	2018-07-11	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	RCV000196735	SCV000254131	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115230	SCV000537555	likely benign	Hereditary cancer-predisposing syndrome	2020-01-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212044	SCV000694327	benign	not specified	2022-04-01	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6543G>T (p.Glu2181Asp) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251444 control chromosomes (gnomAD), predominantly at a frequency of 0.0022 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing the Breast Cancer phenotype (0.001), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. In addition, the variant was found in 8/2559 African American women (allele frequency: 0.001563) older than 70 years of age, who had no history of cancer (FLOSSIES database). c.6543G>T has also been reported in the literature in individuals affected with Breast Cancer (e.g. Bernstein 2010, Haiman_2013, Tung 2016, Adedokun_2020, George_2021, Sandoval_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with a pathogenic variant ATM c.3049C>T (p.Gln1017X) has been seen multiple times in our lab, providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance, and two as likely benign. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
Eurofins Ntd Llc (ga)	RCV000587205	SCV000703945	uncertain significance	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003492464	SCV000838576	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212044	SCV002070968	uncertain significance	not specified	2017-10-09	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225324	SCV002504755	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115230	SCV002537947	likely benign	Hereditary cancer-predisposing syndrome	2021-04-21	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587205	SCV002774765	likely benign	not provided	2022-11-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589571	SCV005084800	likely benign	Familial cancer of breast	2024-06-06	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].
PreventionGenetics, part of Exact Sciences	RCV004549564	SCV004107343	uncertain significance	ATM-related disorder	2024-03-07	no assertion criteria provided	clinical testing	The ATM c.6543G>T variant is predicted to result in the amino acid substitution p.Glu2181Asp. This variant has been previously reported in individuals with breast cancer (see for example Bernstein et al. 2010. PubMed ID: 20305132, Supplementary Table 2; Tung et al. 2016. PubMed ID: 26976419; Adedokun et al. 2020. PubMed ID: 31871109) and endometrial cancer (Lu et al. 2015. PubMed ID: 26689913, Supplementary Data 12). This variant is reported in 0.20% of alleles in individuals of African descent in gnomAD, an allele frequency that is likely too high for a disease causing variant. In ClinVar, this variant has conflicting interpretations regarding its pathogenicity, ranging from benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127425/). Although we suspect this variant may be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.