ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6198+1G>A (rs778031266)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222023 SCV000276351 pathogenic Hereditary cancer-predisposing syndrome 2015-06-05 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbSNP, ESP, 1000 Genomes);in silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (B-level) evidence supporting pathogenicity
GeneDx RCV000519640 SCV000617371 likely pathogenic not provided 2017-03-09 criteria provided, single submitter clinical testing The c.6198+1G>A variant in the ATM gene has been reported previously in at least two individuals with hereditary breast and ovarian cancer and has also been reported along with another ATM variant in at least two individuals reported to have ataxia-telangiectasia (Stankovic et al., 1998; Reiman et al., 2011; Exley et al., 2011; Caminsky et al., 2016). This splice site variant destroys the canonical splice donor site in intron 42 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. The c.6198+1G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.6198+1G>A as a likely pathogenic variant.
Counsyl RCV000668415 SCV000793009 pathogenic Ataxia-telangiectasia syndrome 2017-07-25 criteria provided, single submitter clinical testing
Academic Department of Medical Genetics, University of Cambridge RCV000222023 SCV000992203 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Invitae RCV000668415 SCV001233605 pathogenic Ataxia-telangiectasia syndrome 2019-09-11 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 42 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs778031266, ExAC 0.002%). Variants affecting this donor splice site have been observed as homozygous or in combination with another ATM variant in several individuals affected with ataxia telangiectasia (PMID: 9463314, 21459046, 26915675, 26220245). In addition, it has been reported as heterozygous in individuals affected with ATM-related cancers (PMID: 29909963, 16832357, 21792198). This variant is also known as IVS44+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 221911). 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. 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). For these reasons, this variant has been classified as Pathogenic.
Color RCV000222023 SCV001340920 likely pathogenic Hereditary cancer-predisposing syndrome 2019-06-21 criteria provided, single submitter clinical testing
Dr. Peter K. Rogan Lab,Western University RCV000416815 SCV000262588 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-22 no assertion criteria provided research Sequenced patient with familial breast cancer

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