Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001857777 | SCV002164418 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2016-01-17 | criteria provided, single submitter | clinical testing | In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PMS2-related disease. However, the frequency data is considered unreliable due to the presence of a pseudogene that has strong homology to this region. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This sequence change replaces aspartic acid with glycine at codon 699 of the PMS2 protein (p.Asp699Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. |
Color Diagnostics, |
RCV003584575 | SCV004359555 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-19 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with glycine at codon 699 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. 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). A different variant affecting the same codon, c.2095G>C (p.Asp699His), is considered to be disease-causing (ClinVar variation ID: 140847), suggesting that aspartic acid at this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |