Submissions for variant NM_000051.4(ATM):c.3077+4G>A

gnomAD frequency: 0.00014  dbSNP: rs201222237

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213394	SCV000275928	likely benign	Hereditary cancer-predisposing syndrome	2019-09-05	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.
GeneDx	RCV000430951	SCV000512152	benign	not specified	2015-04-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000988671	SCV000546998	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000430951	SCV000694248	likely benign	not specified	2023-07-02	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3077+4G>A 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 5.6e-05 in 250438 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (5.6e-05 vs 0.004), allowing no conclusion about variant significance. c.3077+4G>A has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual with colorectal cancer who underwent clinical genetic testing for Lynch syndrome (example, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or ATM-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25980754). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as likely benign (n=5) (VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000213394	SCV000903068	likely benign	Hereditary cancer-predisposing syndrome	2016-02-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000988671	SCV001138482	uncertain significance	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000213394	SCV002535312	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-18	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000430951	SCV004220921	likely benign	not specified	2024-06-25	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools yielded predictions that this variant is unlikely to have an effect on normal RNA splicing. This nucleotide position exhibits low evolutionary conservation.
Myriad Genetics, Inc.	RCV004589979	SCV005083288	benign	Familial cancer of breast	2024-05-13	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. 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].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355758	SCV001550726	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM c.3077+4G>A variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch Syndrome associated cancer or colorectal polyps (Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs201222237) as “With Uncertain significance allele” and ClinVar (4x as benign by GeneDx, as likely benign by Invitae, as uncertain significance by Ambry Genetics and Integrated Genetics). The variant was not identified in Cosmic, MutDB, LOVD 3.0 or ATM-LOVD databases. The variant was identified in control databases in 17 of 276132 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 16 of 23934 chromosomes (freq: 0.00067) and Latino in 1 of 34378 chromosomes (freq: 0.00003). It was not observed in the “Other”, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish or South Asian populations. This variant was identified in our laboratory with a co-occurring pathogenic BRCA2 variant (c.3455T>G, p.Leu1152*), increasing the likelihood that the c.3077+4G>A variant does not have clinical significance. The c.3077+4G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% increased difference in splicing 3 bp upstream at the consensus splice junction. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Natera, Inc.	RCV000988671	SCV002079710	likely benign	Ataxia-telangiectasia syndrome	2020-01-19	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004547547	SCV004783697	likely benign	ATM-related disorder	2022-02-03	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).