Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000464576 | SCV000552042 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-11-18 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 802 of the PMS2 protein (p.Arg802Gln). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. 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: 411071). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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. |
| Mendelics | RCV000708978 | SCV000838167 | uncertain significance | Lynch syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001192583 | SCV001360814 | uncertain significance | not specified | 2022-05-05 | criteria provided, single submitter | clinical testing | Variant summary: PMS2 c.2405G>A (p.Arg802Gln) results in a conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-06 in 224314 control chromosomes. 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.2405G>A in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001800681 | SCV002046370 | uncertain significance | not provided | 2020-11-20 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002451130 | SCV002738563 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-28 | criteria provided, single submitter | clinical testing | The p.R802Q variant (also known as c.2405G>A), located in coding exon 14 of the PMS2 gene, results from a G to A substitution at nucleotide position 2405. The arginine at codon 802 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). 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. |
| Baylor Genetics | RCV003463956 | SCV004205491 | uncertain significance | Lynch syndrome 4 | 2023-08-07 | criteria provided, single submitter | clinical testing |