ClinVar Miner

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

dbSNP: rs778031266
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Total submissions: 10
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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 2023-07-19 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, although 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 with a second ATM mutation in a 22-year-old patient with AT, although phase was not confirmed (Schon K et al. Ann. Neurol., 2019 02;85:170-180). In addition, this mutation was identified in a breast cancer family (Renwick A, Nat. Genet. 2006 Aug; 38(8):873-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Furthermore, this nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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 pathogenic not provided 2022-03-16 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Identified in the homozygous state or with a second ATM variant in individuals with ataxia telangiectasia or other ATM-related disorders, including patients exhibiting reduced ATM protein and kinase activity (Stankovic 1998, Exley 2011, Reiman 2011, Al-Mousa 2016, Schon 2019, Amirifar 2021); Observed in the heterozygous state in individuals with breast and other cancers (Renwick 2006, Caminsky 2016, Whitworth 2018, Dorling 2021); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS44+1G>A; This variant is associated with the following publications: (PMID: 9463314, 21459046, 26898890, 21792198, 33471991, 33547824, 26915675, 16832357, 29909963, 30549301, 26220245)
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 2023-11-06 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. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs778031266, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with ataxia telangiectasia. In addition, it has been reported as heterozygous in individuals affected with ATM-related cancers (PMID: 9463314, 16832357, 21459046, 21792198, 26220245, 26915675, 29909963, 30549301). This variant is also known as IVS44+1G>A. 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. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000222023 SCV001340920 likely pathogenic Hereditary cancer-predisposing syndrome 2022-03-08 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +1 position of intron 42 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual with a family history and/or affected with hereditary breast and ovarian cancer (PMID: 26898890). This variant has also been reported in multiple individuals with ataxia-telangiectasia, with at least one case confirmed in trans with a known pathogenic mutation in ATM (PMID: 9463314, 21459046, 21792198, 30549301, 33547824). This variant has been identified in 1/251016 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center RCV001814117 SCV001755559 pathogenic Abnormal central motor function 2021-07-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668415 SCV002103583 pathogenic Ataxia-telangiectasia syndrome 2022-02-14 criteria provided, single submitter clinical testing Variant summary: ATM c.6198+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251016 control chromosomes. c.6198+1G>A has been reported in the literature in individuals affected with Ataxia-Telangiectasia, multiple primary tumor, or breast cancer (e.g. Stankovic_1998, Whitworth_2018, Schon_2019, Dorling_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003468967 SCV004212105 pathogenic Familial cancer of breast 2023-01-24 criteria provided, single submitter clinical testing
Dr. Peter K. Rogan Lab, Western University RCV000416815 SCV000262588 likely pathogenic Hereditary breast ovarian cancer syndrome 2015-12-22 no assertion criteria provided research Sequenced patient with familial breast cancer

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