ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8786+1G>C (rs17174393)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166748 SCV000217559 pathogenic Hereditary cancer-predisposing syndrome 2019-08-27 criteria provided, single submitter clinical testing Well-characterized mutation at same position;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Invitae RCV000196816 SCV000253748 pathogenic Ataxia-telangiectasia syndrome 2019-10-31 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 60. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been published in the literature, however a different nucleotide change at this position (c.8786+1G>A), which has been predicted by algorithms to alter mRNA splicing, was reported in an individual affected with ataxia-telangiectasia (PMID: 8808599) and multiple individuals affected with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 187060). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this c.8786+1G>C intronic variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000254910 SCV000322521 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing This variant is denoted ATM c.8786+1G>C or IVS60+1G>C and consists of a G>C nucleotide substitution at the +1 position of intron 60 of the ATM gene. This variant destroys a canonical splice donor 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 at least one individual with prostate cancer (Mandelker 2017). Additionally, a G>A nucleotide substitution at the same position (ATM c.8786+1G>A, also reported as IVS62+1G>A using alternate exon numbering) has been reported in the compound heterozygous state with a second truncating ATM variant in several individuals with Ataxia-telangiectasia (Stankovic 1998, Teraoka 1999). Based on the current evidence, we consider ATM c.8786+1G>C to be pathogenic.

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