Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000820699 | SCV000961422 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2018-10-02 | 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 271 of the PMS2 protein (p.Gly271Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. |
| Color Diagnostics, |
RCV001524409 | SCV001734237 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-21 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with serine at codon 271 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in an individual affected with endometrial and colorectal cancer that demonstrated loss of MLH1 and PMS2 proteins via immunohistochemistry analysis (PMID: 34048176). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.811G>C (p.Gly271Arg), has been described to be disease-causing (ClinVar variation ID: 1762082), supporting that this position is important for the protein function. 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. |
| Ambry Genetics | RCV001524409 | SCV003853894 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-12 | criteria provided, single submitter | clinical testing | The p.G271S variant (also known as c.811G>A), located in coding exon 8 of the PMS2 gene, results from a G to A substitution at nucleotide position 811. The glycine at codon 271 is replaced by serine, an amino acid with similar properties. This variant was identified in a Thai patient with synchronous colon and endometrial cancers at 51; the endometrial tumor demonstrated loss of MLH1 and PMS2 expression by IHC (Manchana T et al. Asian Pac J Cancer Prev, 2021 May;22:1477-1483). This variant was reported as somatic in the liver metastases of a patient with a germline PMS2 mutation (designated R134*) who was diagnosed with PMS2- colorectal cancer at age 41 (Moreno E et al. Diagn Pathol, 2020 Jul;15:84). 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. |