Submissions for variant NM_000051.4(ATM):c.6176C>T (p.Thr2059Ile)

gnomAD frequency: 0.00126  dbSNP: rs144761622

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588663	SCV000149135	likely benign	not provided	2021-06-05	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28135145, 27443514, 25186627, 19781682, 12917204, 17333338, 17517479, 20305132, 17623063, 23555315)
Ambry Genetics	RCV000115226	SCV000186819	likely benign	Hereditary cancer-predisposing syndrome	2019-07-08	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	RCV000196722	SCV000252969	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212040	SCV000593505	uncertain significance	not specified	2016-09-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212040	SCV000694319	benign	not specified	2021-06-21	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6176C>T (p.Thr2059Ile) results in a non-conservative amino acid change located in the PIK-related kinase (IPR014009) 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 0.00023 in 251306 control chromosomes, predominantly at a frequency of 0.0033 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 3.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Consistently, this variant is observed at a frequency of 22/9884 subjects to include 21 women of African American ancestry (0.002226) in the FLOSSIES database of cancer free women at age 70. c.6176C>T has been reported in the literature in settings of multgene cancer panel testing in controls as well as patients with a variety of cancers to include breast, colorectal, endometrial and therapy related myeloid neoplasms without strong evidence for pathogenicity (example, Ho_2007, Edvardsen_2007, Bretsky_2003, Hirsch_2008, Bernstein_2010, Ring_2016, Yurgelun_2017, Tung_2015, Singhal_2021). This variant was reported as a germline VUS to co-occur with a WT1 variant of somatic origin (c.1137dup, p.R380Tfs*5) in one case of therapy related myeloid neoplasm (Singhal_2021). At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.5042_5043delTG, p.Val1681fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=3; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation and at-least one additional submitter has re-classified this variant from a VUS to likely benign since its previous evaluation. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV003492463	SCV000838567	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115226	SCV000902666	likely benign	Hereditary cancer-predisposing syndrome	2015-09-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000196722	SCV001481632	uncertain significance	Ataxia-telangiectasia syndrome	2019-10-08	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225323	SCV002504746	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115226	SCV002537155	likely benign	Hereditary cancer-predisposing syndrome	2021-05-29	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212040	SCV004221230	likely benign	not specified	2023-09-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene.
Myriad Genetics, Inc.	RCV004589570	SCV005084037	likely benign	Familial cancer of breast	2024-06-03	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	RCV004549562	SCV000805596	likely benign	ATM-related disorder	2024-05-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV000196722	SCV001466201	uncertain significance	Ataxia-telangiectasia syndrome	2020-04-03	no assertion criteria provided	clinical testing