Submissions for variant NM_000051.4(ATM):c.1066-3_1072del

dbSNP: rs1591517089

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808362	SCV000948469	likely pathogenic	Ataxia-telangiectasia syndrome	2023-11-03	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 9 (c.1066-3_1072del) 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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 652741). 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.
Ambry Genetics	RCV001009826	SCV001169940	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	The c.1066-3_1072del10 variant results from a deletion of 10 nucleotides between positions c.1066-3 to c.1072 and involves the canonical splice acceptor site before coding exon 8 of the ATM gene. The canonical splice acceptor site is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor 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 or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Myriad Genetics, Inc.	RCV004028646	SCV004933140	likely pathogenic	Familial cancer of breast	2024-01-12	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.
GeneDx	RCV004719997	SCV005325343	likely pathogenic	not provided	2024-03-12	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); Observed in a patient with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754); This variant is associated with the following publications: (PMID: 25980754)