Submissions for variant NM_000051.4(ATM):c.3588A>G (p.Lys1196=)

gnomAD frequency: 0.00006  dbSNP: rs376524625

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163406	SCV000213948	likely benign	Hereditary cancer-predisposing syndrome	2014-07-10	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	RCV000205348	SCV000259717	likely benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163406	SCV000682148	likely benign	Hereditary cancer-predisposing syndrome	2017-06-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779757	SCV000916533	likely benign	not specified	2023-12-21	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3588A>G results in a synonymous change. Consensus agreement among computation 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 8.5e-05 in 1613030 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.5e-05 vs 0.004), allowing no conclusion about variant significance. c.3588A>G has been reported in the literature (Buzin 2003, Decker 2017); however these reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. 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: 12552559, 28779002). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001711328	SCV001939422	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163406	SCV002536506	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-30	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV004589710	SCV005083299	benign	Familial cancer of breast	2024-05-15	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.
PreventionGenetics, part of Exact Sciences	RCV004551395	SCV004732898	likely benign	ATM-related disorder	2022-02-24	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).