Submissions for variant NM_000051.4(ATM):c.2467-1G>A

dbSNP: rs1328985852

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000539233	SCV000622332	likely pathogenic	Ataxia-telangiectasia syndrome	2023-09-06	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 16 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 (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 453416). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260447	SCV001437454	likely pathogenic	Malignant tumor of breast	2020-09-28	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2467-1G>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 canonical 3 acceptor site. Four predict the variant creates a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251164 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2467-1G>A in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV003225078	SCV003921423	likely pathogenic	not provided	2022-10-27	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; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003470665	SCV004212073	likely pathogenic	Familial cancer of breast	2023-03-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004678733	SCV005169413	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-04-16	criteria provided, single submitter	clinical testing	The c.2467-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 16 of the ATM gene. 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 acceptor site and will result in the creation or strengthening of a novel splice acceptor site. 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.