Submissions for variant NM_000051.4(ATM):c.2466+7A>G

gnomAD frequency: 0.00008  dbSNP: rs55812024

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000123729	SCV000167072	benign	not specified	2014-01-30	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.
Invitae	RCV000199567	SCV000252948	benign	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000581086	SCV000682058	likely benign	Hereditary cancer-predisposing syndrome		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000123729	SCV000918560	benign	not specified	2018-09-07	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2466+7A>G 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. 5/5 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 0.00032 in 275780 control chromosomes, predominantly at a frequency of 0.0046 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.2466+7A>G in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000581086	SCV002532189	benign	Hereditary cancer-predisposing syndrome	2021-01-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000123729	SCV004027179	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952638	SCV004769300	likely benign	ATM-related condition	2019-12-13	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001311784	SCV001551296	likely benign	not provided		no assertion criteria provided	clinical testing	The ATM c.2466+7A>G variant was not identified in the literature nor was it identified in the following databases: GeneInsight-COGR, Cosmic, MutDB, or LOVD 3.0. The variant was identified in dbSNP (ID: rs55812024) as "With Benign allele", ClinVar (1x benign, 1x likely benign), and Clinvitae databases. The variant was identified in control databases in 89 of 275780 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Latino in 3 of 34346 chromosomes (freq: 0.00009) and East Asian in 86 of 18806 chromosomes (freq: 0.005), while the variant was not observed in the African, Other, European, Ashkenazi Jewish, Finnish, or South Asian populations. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of 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.