Submissions for variant NM_000051.4(ATM):c.2919A>G (p.Leu973=)

gnomAD frequency: 0.00005  dbSNP: rs587779829

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211990	SCV000149075	uncertain significance	not provided	2021-06-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in individuals with personal and/or family history of breast cancer, but also in healthy controls (Decker 2017, Kraus 2017, Tiao 2017); This variant is associated with the following publications: (PMID: 27616075, 28779002, 28652578, 27535533)
Ambry Genetics	RCV000115166	SCV000214809	likely benign	Hereditary cancer-predisposing syndrome	2016-03-15	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	RCV000463962	SCV000558329	likely benign	Ataxia-telangiectasia syndrome	2024-01-26	criteria provided, single submitter	clinical testing
Counsyl	RCV000463962	SCV000790742	likely benign	Ataxia-telangiectasia syndrome	2017-04-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115166	SCV000903204	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	RCV004525873	SCV005039572	uncertain significance	not specified	2024-03-11	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2919A>G (p.Leu973Leu) 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. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.6e-05 in 251358 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Although reported as a VUS in settings of multigene panel testing for Inherited cancers (example, Kraus_2016, Okawa_2023), to our knowledge, no occurrence of c.2919A>G in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27616075, 36243179). ClinVar contains an entry for this variant (Variation ID: 127361). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Myriad Genetics, Inc.	RCV004589559	SCV005084641	benign	Familial cancer of breast	2024-05-10	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355592	SCV001550518	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Leu973= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, databases. The variant was identified in the following databases: dbSNP (ID: rs587779829) as With “Uncertain significance allele”, ClinVar (reported 3x, as likely benign by Ambry Genetics, Invitae and uncertain significance by GeneDx), Clinvitae (reported 3x). The variant was identified in control databases in 11 of 277110 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2 of 24014 chromosomes (freq: 0.00008), European Non-Finnish in 7 of 126668 chromosomes (freq: 0.000055), and South Asian in 2 of 30778 chromosomes (freq: 0.000065). while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, populations. This variant was identified by our laboratory with a co-occurring pathogenic BRCA2 variant (c.5350_5351delAA, p.Asn1784Hisfsx2), increasing the likelihood that the p.Leu973= variant does not have clinical significance. The p.Leu973= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004549544	SCV004758339	likely benign	ATM-related disorder	2019-12-24	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).