Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001063621 | SCV001228477 | likely pathogenic | Ataxia-telangiectasia syndrome | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 34 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 26896183). ClinVar contains an entry for this variant (Variation ID: 857860). Studies have shown that disruption of this splice site results in skipping of exon 34 (also known as exon 36) and introduces a premature termination codon (PMID: 18497957). The resulting mRNA is expected to undergo nonsense-mediated decay. 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. |
| Illumina Laboratory Services, |
RCV001563590 | SCV001786564 | pathogenic | ATM-related disorders | 2021-02-05 | criteria provided, single submitter | clinical testing | The ATM c.5177+1G>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. This variant is not found in the Genome Aggregation Database in a region of good sequence coverage and hence is presumed to be rare. Soukupova et al. (2008), identified the c.5177+1G>A variant, a different nucleotide change at the same position, in a heterozygous state in a patient with bilateral breast cancer (ages: 42 and 44 years). Quantitative analysis of RNA samples from the patient indicated that the c.5177+G>A variant caused skipping of exon 36, when compared to controls. The skipping of exon 36 is predicted to cause premature termination at codon 1680 of the ATM protein. Based on the cumulative evidence, the c.5177+1G>C variant is classified as pathogenic for ATM-related disorders. |
| Color Diagnostics, |
RCV003584813 | SCV004361017 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-12-15 | criteria provided, single submitter | clinical testing | This variant causes a G to C nucleotide substitution at the +1 position of intron 34 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional RNA studies have not been reported for this variant, it is expected to disrupt RNA splicing and result in an absent or non-functional protein product. A different variant at the same position, c.5177+1G>A, has been identified in an individual affected with bilateral breast cancer and family history of pancreatic and breast cancer (PMID: 18497957). An RNA study using cells from this heterozygous individual has shown that c.5177+1G>A variant results in exon 34 skipping (referred to as exon 36 in the article based on the U33841 transcript) and premature protein truncation, with almost no expression of normal transcripts from the mutant allele (PMID: 18497957). This c.5177+1G>C variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. |