Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000130789 | SCV000185682 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-11-30 | criteria provided, single submitter | clinical testing | The p.E422K variant (also known as c.1264G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1264. The glutamic acid at codon 422 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV000204417 | SCV000261426 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-19 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 422 of the PMS2 protein (p.Glu422Lys). This variant is present in population databases (rs587782175, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 142008). 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 expected to disrupt PMS2 protein function with a positive predictive value of 80%. 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. |
Color Diagnostics, |
RCV000130789 | SCV000686114 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-31 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with lysine at codon 422 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 4/251060 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000590135 | SCV000697291 | uncertain significance | not provided | 2017-03-16 | criteria provided, single submitter | clinical testing | Variant summary: The PMS2 c.1264G>A (p.Glu422Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). The variant of interest is absent in the large, broad control population, ExAC. The variant is not in any known functional domain of the protein (InterPro). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. |
Gene |
RCV000590135 | SCV001820283 | uncertain significance | not provided | 2021-05-03 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
Baylor Genetics | RCV003462001 | SCV004205353 | uncertain significance | Lynch syndrome 4 | 2023-10-25 | criteria provided, single submitter | clinical testing |