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 2020-03-04 criteria provided, single submitter clinical testing The c.6198+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 41 of the ATM gene. This mutation was detected in two ataxia-telangiectasia (AT) patients, though a second pathogenic ATM mutation was not detected in either individual (Stankovic T et al, Am. J. Hum. Genet. 1998 Feb; 62(2):334-45; Reiman A, Br. J. Cancer 2011 Aug; 105(4):586-91). However, this mutation was subsequently identified in the homozygous state in a child with AT, as well as in the compound heterozygous state with second ATM mutation in a 22-year-old patient with AT (Rawat A, Indian J Pediatr 2015 Jul; Schon K et al. Ann. Neurol., 2019 02;85:170-180). In addition, this mutation has been identified in a breast cancer family (Renwick A, Nat. Genet. 2006 Aug; 38(8):873-5). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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.
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 2020-03-12 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 Health, Inc 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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