Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000199090 | SCV000254599 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-30 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 519 of the PMS2 protein (p.Tyr519His). This variant is present in population databases (rs370236216, 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: 216451). 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 with a negative 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. |
| Ambry Genetics | RCV000221963 | SCV000273557 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-08 | criteria provided, single submitter | clinical testing | The p.Y519H variant (also known as c.1555T>C), located in coding exon 11 of the PMS2 gene, results from a T to C substitution at nucleotide position 1555. The tyrosine at codon 519 is replaced by histidine, an amino acid with similar properties. This amino acid position is poorly 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 this alteration remains unclear. |
| Gene |
RCV000486619 | SCV000565409 | uncertain significance | not provided | 2023-11-13 | 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 |
| Color Diagnostics, |
RCV000221963 | SCV000903477 | likely benign | Hereditary cancer-predisposing syndrome | 2016-05-02 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780620 | SCV000918042 | uncertain significance | not specified | 2019-08-13 | criteria provided, single submitter | clinical testing | Variant summary: PMS2 c.1555T>C (p.Tyr519His) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251302 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.1555T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance (3x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Mendelics | RCV000987826 | SCV001137293 | uncertain significance | Lynch syndrome 4 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000486619 | SCV002774697 | uncertain significance | not provided | 2021-08-11 | criteria provided, single submitter | clinical testing |