Submissions for variant NM_000051.4(ATM):c.8585-2A>C

dbSNP: rs1060501700

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221539	SCV002499304	pathogenic	Familial cancer of breast	2022-03-09	reviewed by expert panel	curation	The ATM c.8585-2A>C variant is predicted to result in a truncated protein that disrupts a critical functional domain (PVS1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals with Ataxia-Telangiectasia (PM3_Strong; PMID: 23322442, PMID: 29665859). This variant is absent in the gnomAD v2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462876	SCV000547126	likely pathogenic	Ataxia-telangiectasia syndrome	2019-10-08	criteria provided, single submitter	clinical testing	Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported in the literature in an individual affected with ataxia-telangectasia (PMID: 23322442). ClinVar contains an entry for this variant (Variation ID: 407718). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 58 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
GeneDx	RCV000482474	SCV000568339	likely pathogenic	not provided	2017-01-25	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.8585-2A>C or IVS58-2A>C and consists of an A>C nucleotide substitution at the -2 position of intron 58 of the ATM gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in the homozygous state in an individual with Ataxia-Telangiectasia (Jeddane 2013). Based on the currently available information, we consider ATM c.8585-2A>C to be a likely pathogenic variant.
Mendelics	RCV000462876	SCV001138582	likely pathogenic	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001018039	SCV001179217	pathogenic	Hereditary cancer-predisposing syndrome	2019-10-01	criteria provided, single submitter	clinical testing	The c.8585-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 58 in the ATM gene. This alteration was observed in the homozygous state in a Moroccan patient with ataxia-telangiectasia (Jeddane L et al. Neuromolecular Med., 2013 Jun;15:288-94). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Myriad Genetics, Inc.	RCV002221539	SCV004930652	pathogenic	Familial cancer of breast	2024-02-02	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. Functional studies indicate this variant impacts protein function [PMID: 22006793]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22006793, 23322442, 21665257, 31741144].