Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781749 | SCV000920039 | uncertain significance | not specified | 2018-10-19 | criteria provided, single submitter | clinical testing | Variant summary: PMS2 c.1270T>C (p.Phe424Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276788 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1270T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Ambry Genetics | RCV002370056 | SCV002686300 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-10-21 | criteria provided, single submitter | clinical testing | The p.F424L variant (also known as c.1270T>C), located in coding exon 11 of the PMS2 gene, results from a T to C substitution at nucleotide position 1270. The phenylalanine at codon 424 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. 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 this alteration remains unclear. |
| Invitae | RCV003594039 | SCV004318485 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-08-17 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 633368). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMS2 protein function. This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 424 of the PMS2 protein (p.Phe424Leu). |