Submissions for variant NM_000051.4(ATM):c.4776+2_4776+13del

dbSNP: rs762838462

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482221	SCV000568671	likely pathogenic	not provided	2015-11-13	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.4776+2_4776+13del12 or IVS31+2_IVS31+13del12 and consists of a deletion of 12 nucleotides from the +2 to +13 positions of intron 31. The normal sequence, with the bases that are deleted in braces, is GAGg[del12]catc, where the capital letters are exonic and lowercase are intronic. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature. Based on the currently available information, we consider ATM c.4776+2_4776+13del12 to be likely pathogenic.
Invitae	RCV000536317	SCV000622530	pathogenic	Ataxia-telangiectasia syndrome	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 31 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 (rs762838462, gnomAD 0.0009%). 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: 420098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000582357	SCV000687568	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	clinical testing	This variant causes a 12 nucleotide deletion affecting a canonical splice site in intron 31 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/249594 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 Likely Pathogenic.
Ambry Genetics	RCV000582357	SCV002634726	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-05	criteria provided, single submitter	clinical testing	The c.4776+2_4776+13del12 intronic pathogenic mutation, located in intron 30 of the ATM gene, results from a deletion of 12 nucleotides within intron 30 of the ATM gene. This nucleotide region is well 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, multiple ATM mutations affecting this canonical splice donor site (c.4776+2T>C, c.4776+2T>A, c.4776+2T>C), have been reported in patients with ataxia telangiectasia and have also been shown to result in skipping of coding exon 30 (Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62(3):551-61; Ejima Y et al. Hum. Genet., 1998 Apr;102:403-8; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 a disease-causing mutation.
Baylor Genetics	RCV003464008	SCV004213910	likely pathogenic	Familial cancer of breast	2022-04-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003464008	SCV004930340	likely pathogenic	Familial cancer of breast	2024-01-24	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.