Submissions for variant NM_000051.4(ATM):c.103C>A (p.Arg35=)

gnomAD frequency: 0.00032  dbSNP: rs55861249

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162607	SCV000213034	likely benign	Hereditary cancer-predisposing syndrome	2014-11-25	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	RCV001084288	SCV000282858	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000242698	SCV000301649	likely benign	not specified		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162607	SCV000681948	likely benign	Hereditary cancer-predisposing syndrome	2015-08-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000242698	SCV000694168	likely benign	not specified	2023-08-24	criteria provided, single submitter	clinical testing	Variant summary: ATM c.103C>A alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.9e-05 in 282600 control chromosomes (gnomAD), predominantly at a frequency of 0.00088 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 (9.9e-05 vs 0.001), allowing no conclusion about variant significance. c.103C>A has been reported in the literature without evidence for causality (e.g. Gumy Pause_2003, Bernstein_2010). These reports 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: 20305132, 12673804). Ten ClinVar submitters have assessed the variant since 2014: one classified the variant as benign, and nine as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000589960	SCV001148397	likely benign	not provided	2019-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000589960	SCV001939415	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000242698	SCV002070310	likely benign	not specified	2020-07-15	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225474	SCV002504902	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162607	SCV002529685	likely benign	Hereditary cancer-predisposing syndrome	2020-11-30	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149989	SCV003837824	likely benign	Breast and/or ovarian cancer	2022-04-06	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315979	SCV004017258	likely benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315979	SCV005083824	benign	Familial cancer of breast	2024-04-17	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Natera, Inc.	RCV001084288	SCV001461803	likely benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing