Submissions for variant NM_000051.4(ATM):c.2376+1G>T

dbSNP: rs730881347

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159692	SCV000209700	likely pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in a patient with prostate cancer (PMID: 33436325); This variant is associated with the following publications: (PMID: 26681312, 22213089, 33436325)
Ambry Genetics	RCV000568382	SCV000665588	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-04	criteria provided, single submitter	clinical testing	The c.2376+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 14 of the ATM gene. A different mutation affecting the same nucleotide, c.2376+1G>A, has been reported in a compound heterozygous state in an individual with ataxia-telangiectasia (Verhagen MM et al. Hum. Mutat., 2012 Mar;33:561-71). 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). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. As such, this alteration is classified as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810067	SCV000950254	likely pathogenic	Ataxia-telangiectasia syndrome	2022-12-31	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 181927). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with clinical features of ATM-related conditions (PMID: 22213089, 26681312). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 15 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).