Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000700268 | SCV000829016 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-01-02 | criteria provided, single submitter | clinical testing | This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 433 of the PMS2 protein (p.Lys433Glu). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. 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. 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: 577493). |
Ambry Genetics | RCV002386238 | SCV002692405 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-09-08 | criteria provided, single submitter | clinical testing | The p.K433E variant (also known as c.1297A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1297. The lysine at codon 433 is replaced by glutamic acid, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6500 samples (13000 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 65000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.K433E remains unclear. |
All of Us Research Program, |
RCV003999704 | SCV004828113 | uncertain significance | Lynch syndrome | 2023-08-28 | criteria provided, single submitter | clinical testing | This missense variant replaces lysine with glutamic acid at codon 433 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 been identified in 1/251074 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. |