Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV002387394 | SCV002695806 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-07-11 | criteria provided, single submitter | clinical testing | The c.988+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 9 in the PMS2 gene. This nucleotide position is highly conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
All of Us Research Program, |
RCV004007294 | SCV004834563 | likely pathogenic | Lynch syndrome | 2024-02-05 | criteria provided, single submitter | clinical testing | This variant causes a T to C nucleotide substitution at the +2 position of intron 9 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same +1/2 canonical splice donor site, c.988+1G>C and c.988+1G>T, are known to be disease-causing (ClinVar variation ID: 1499988, 968704). Loss of PMS2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. |