ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1065+1G>T (rs201089102)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166070 SCV000216833 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-15 criteria provided, single submitter clinical testing The c.1065+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 7 of the ATM gene. This nucleotide position is highly conserved in available vertebrate species. This alteration was reported in 1/7051 Japanese female breast cancer cases, and was not detected in 11241 controls (Momozowa Y et al. Nat Commun 2018 10;9(1):4083). This alteration has also been reported with an individual with lung cancer at age 53 and later pancreatic cancer at 62 (Slavin TP et al. Fam. Cancer, 2018 04;17:235-245). Using two different splice site prediction tools, this alteration is predicted by ESEfinder to abolish the native splice donor site, but BDGP does not produce a reliable prediction for the nearby splice donor site. Using the Human Splicing Finder (HSF) splice site prediction tool, this alteration is predicted to weaken the native splice donor site (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as likely pathogenic.
Counsyl RCV000411731 SCV000487262 likely pathogenic Ataxia-telangiectasia syndrome 2016-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000436210 SCV000517272 pathogenic not provided 2019-06-10 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28687971)
Color Health, Inc RCV000166070 SCV000537619 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-29 criteria provided, single submitter clinical testing This variant causes a G to T nucleotide substitution at the +1 position of intron 8 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with lung and pancreatic cancer (PMID: 28687971). This variant has not been identified 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.
Invitae RCV000411731 SCV000547061 likely pathogenic Ataxia-telangiectasia syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the ATM gene. It is expected to disrupt RNA 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 been observed in an individual affected with lung and pancreatic cancer (PMID: 28687971). ClinVar contains an entry for this variant (Variation ID: 186470). 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.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000411731 SCV000781078 likely pathogenic Ataxia-telangiectasia syndrome 2016-11-01 criteria provided, single submitter clinical testing
Mendelics RCV000411731 SCV000838481 likely pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420920 SCV001623371 likely pathogenic Malignant tumor of breast 2021-04-24 criteria provided, single submitter clinical testing Variant summary: ATM c.1065+1G>T 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: Three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250980 control chromosomes. c.1065+1G>T has been reported in the literature in at-least one individual affected with lung cancer and Pancreatic ductal adenocarcinoma (example, Slavin_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 likely pathogenic.

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