Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000475054 | SCV000552046 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2021-11-09 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 736 of the PMS2 protein (p.Glu736Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function. ClinVar contains an entry for this variant (Variation ID: 411073). A variant with the same transcript coordinates as this variant (c.2207A>T) has been reported in the literature in a family affected with Lynch syndrome that also had a pathogenic p.Leu731* variant on the same PMS2 allele (PMID: 25430799). However, the description of the protein effect for this c.2207A>T variant is discordant, making it unclear if this is truly the same variant. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. |