Submissions for variant NM_000051.4(ATM):c.3154-5C>T

gnomAD frequency: 0.00004  dbSNP: rs55719759

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129749	SCV000184555	likely benign	Hereditary cancer-predisposing syndrome	2018-10-19	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	RCV000462650	SCV000558392	likely benign	Ataxia-telangiectasia syndrome	2025-01-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000462650	SCV000838517	benign	Ataxia-telangiectasia syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129749	SCV000911173	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	RCV000779795	SCV000916599	likely benign	not specified	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3154-5C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 0.00047 in 328526 control chromosomes, predominantly in Japanese population (0.0019). This frequency is slightly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.001), suggesting this variant may be benign. c.3154-5C>T has been reported in the literature in individuals affected with Breast Cancer. 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. 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 (benign/likely benign n=4, VUS n=3). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001311785	SCV001884257	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29338689)
Sema4, Sema4	RCV000129749	SCV002533598	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	curation
Athena Diagnostics	RCV001311785	SCV002771626	uncertain significance	not provided	2022-06-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589627	SCV005082075	likely benign	Familial cancer of breast	2024-05-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.