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

dbSNP: rs201089102

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166070	SCV000216833	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-28	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 in 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). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). A published RNA study has also identified abnormal splicing associated with this variant (Bueno-Martínez E et al. J Pathol, 2022 Sep;258:83-101). 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	2022-09-22	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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28687971, 32581083, 35264596, 28888541)
Color Diagnostics, LLC DBA Color Health	RCV000166070	SCV000537619	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-04-05	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 breast cancer (PMID: 32581083) and 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411731	SCV000547061	likely pathogenic	Ataxia-telangiectasia syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with ATM-related cancers (PMID: 28687971, 28888541, 32581083, 35264596). ClinVar contains an entry for this variant (Variation ID: 186470). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
Centogene AG - the Rare Disease Company	RCV000411731	SCV002059549	pathogenic	Ataxia-telangiectasia syndrome	2018-08-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468770	SCV004209518	pathogenic	Familial cancer of breast	2024-02-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468770	SCV004931000	likely pathogenic	Familial cancer of breast	2024-01-11	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.