ClinVar Genomic variation as it relates to human health

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 individuals with a personal and/or family history of breast and ovarian cancer (Tavtigian et al., 2009; Lilyquist et al., 2017); This variant is associated with the following publications: (PMID: 33442023, 28888541, 19781682)

The c.6095+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 40 of the ATM gene. In one study, this variant was reported in two breast cancer patients and was predicted to result in protein truncation due to a defect of the donor splice site (Tavtigian SV et al. Am J Hum Genet. 2009 Oct;85(4):427-46). Based on nucleotide sequence alignment, this 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 or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

Variant summary: ATM c.6095+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 121252 control chromosomes. c.6095+1G>A has been reported in the literature in individuals affected with breast cancer from a meta-analysis of cases and controls (Tavtigian_2009). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change affects a donor splice site in intron 41 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). Disruption of this splice site has been observed in individual(s) with breast cancer, renal cell cancer, ovarian, and pancreatic cancer (PMID: 19781682, 28888541, 33442023, 34284872, 35171259). ClinVar contains an entry for this variant (Variation ID: 141218). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

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.