Submissions for variant NM_000051.4(ATM):c.3352A>G (p.Thr1118Ala)

dbSNP: rs572564322

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211998	SCV000209727	uncertain significance	not provided	2023-10-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or ovarian cancer, but also observed in non-cancer controls in a case-control study of individuals with multiple primary cancers (PMID: 28779002, 33552952, 29641532); This variant is associated with the following publications: (PMID: 19781682, 33552952, 28779002, 29641532)
Ambry Genetics	RCV000159715	SCV000217389	likely benign	Hereditary cancer-predisposing syndrome	2021-05-08	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.
Illumina Laboratory Services, Illumina	RCV000335065	SCV000367045	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000335065	SCV000546834	likely benign	Ataxia-telangiectasia syndrome	2024-01-17	criteria provided, single submitter	clinical testing
Counsyl	RCV000335065	SCV000798489	uncertain significance	Ataxia-telangiectasia syndrome	2018-03-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159715	SCV000910962	likely benign	Hereditary cancer-predisposing syndrome	2015-04-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226222	SCV003922847	likely benign	not specified	2023-03-14	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3352A>G (p.Thr1118Ala) results in a non-conservative amino acid change in 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 0.0002 in 250952 control chromosomes, predominantly at a frequency of 0.0016 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3352A>G has been reported in the literature in individuals affected with Breast Cancer. This report does 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. Seven 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 (likely benign n=3, VUS n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Myriad Genetics, Inc.	RCV004589672	SCV005082723	likely benign	Familial cancer of breast	2024-05-14	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].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003226222	SCV005090236	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000335065	SCV001457139	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing