Submissions for variant NM_000051.4(ATM):c.5496+1G>A

dbSNP: rs879254180

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235522	SCV000293731	likely pathogenic	not provided	2015-12-23	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.5496+1G>A or IVS36+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 36 of the ATM gene. 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. This variant has not, to our knowledge, been published in the literature. Based on the currently available information, we consider ATM c.5496+1G>A to be a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071525	SCV001236833	likely pathogenic	Ataxia-telangiectasia syndrome	2019-12-16	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). 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. Donor and acceptor splice site variants 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 246256). This sequence change affects a donor splice site in intron 36 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics	RCV002347927	SCV002650072	likely pathogenic	Hereditary cancer-predisposing syndrome	2015-11-06	criteria provided, single submitter	clinical testing	The c.5496+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 35 of the ATM gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 125000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.