Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000463324 | SCV000552013 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2020-10-02 | criteria provided, single submitter | clinical testing | 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 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 and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 411058). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 239 of the PMS2 protein (p.Leu239Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. |
Ambry Genetics | RCV002374806 | SCV002662269 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-10-05 | criteria provided, single submitter | clinical testing | The p.L239R variant (also known as c.716T>G), located in coding exon 7 of the PMS2 gene, results from a T to G substitution at nucleotide position 716. The leucine at codon 239 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in an individual diagnosed with a small bowel cancer at 45 (Wang Q et al. J Med Genet, 2020 07;57:487-499). This alteration was also identified in an individual diagnosed with colorectal cancer at 71. Immunohistochemistry on his tumor showed loss of expression of PMS2 (Schwartz A et al. Front Oncol, 2022 Aug;12:942741). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |