Submissions for variant NM_000051.4(ATM):c.2638+2T>C

dbSNP: rs587779826

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211986	SCV000149071	pathogenic	not provided	2022-05-20	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; Observed in an individual with personal or family history of melanoma, thyroid cancer, kidney cancer, colon cancer, and polyps (Shirts 2016); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: exon skipping (Casadei 2019); Observed with a pathogenic variant on the opposite allele (in trans) in multiple sisters with late-onset ataxia telangiectasia (Meneret 2014); Also known as IVS19+2T>C; This variant is associated with the following publications: (PMID: 26681312, 23807571, 28888541, 25614872, 31447099, 31843900, 25122203, 26845104)
Ambry Genetics	RCV000115162	SCV000214719	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-04	criteria provided, single submitter	clinical testing	The c.2638+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 16 in the ATM gene. This alteration has been reported in an individual with breast cancer and in a patient with melanoma, thyroid and kidney cancers (Susswein LR et al. Genet. Med. 2016 08;18(8):823-32; Shirts BH et al. Genet. Med. 2016 10;18(10):974-81). Another alteration at this same nucleotide position has been reported in four related individuals with atypical ataxia-telangiectasia (Méneret A et al. Neurology, 2014 Sep;83:1087-95). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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 likely pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000115162	SCV000266015	likely pathogenic	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Invitae	RCV000477335	SCV000547102	pathogenic	Ataxia-telangiectasia syndrome	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 17 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 present in population databases (rs587779826, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (A-T) and/or melanoma, breast cancer, thyroid cancer and kidney cancer (PMID: 25122203, 26681312, 26845104). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127357). Studies have shown that disruption of this splice site results in skipping exon 17 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000115162	SCV000682067	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +2 position of intron 17 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study has reported that this variant leads to the skipping of exon 17, creating a premature translation stop signal in the RNA transcript (PMID: 31843900). The aberrant transcript is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with breast cancer (PMID: 26681312) and in an individual affected with melanoma, kidney and thyroid cancer (PMID: 26845104). This variant has been identified in 1/251350 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 Pathogenic.
Counsyl	RCV000477335	SCV000794012	pathogenic	Ataxia-telangiectasia syndrome	2017-09-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000211986	SCV000805523	likely pathogenic	not provided	2017-10-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000477335	SCV002021951	pathogenic	Ataxia-telangiectasia syndrome	2019-02-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001171402	SCV004209453	pathogenic	Familial cancer of breast	2023-09-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001171402	SCV004931980	likely pathogenic	Familial cancer of breast	2024-01-18	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.
King Laboratory, University of Washington	RCV001171402	SCV001251306	pathogenic	Familial cancer of breast	2019-09-01	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV003330437	SCV004037517	not provided	Familial cancer of breast; Ataxia-telangiectasia syndrome		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 02-23-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.