Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000576125 | SCV000676170 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-11-16 | criteria provided, single submitter | clinical testing | The p.Y61C variant (also known as c.182A>G), located in coding exon 3 of the PMS2 gene, results from an A to G substitution at nucleotide position 182. The tyrosine at codon 61 is replaced by cysteine, an amino acid with highly dissimilar properties. In a study of patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium, this alteration was observed in the TCGA colorectal adenocarcinoma data set, which was used to represent sporadic cancer (Lee YR et al. N Engl J Med, 2020 05;382:2103-2116). This amino acid position is not well 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. |
| Invitae | RCV000692149 | SCV000819958 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-10 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 61 of the PMS2 protein (p.Tyr61Cys). This variant is present in population databases (rs773109986, gnomAD 0.007%). 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: 486926). 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. 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. |
| Color Diagnostics, |
RCV000576125 | SCV001353843 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-09-25 | criteria provided, single submitter | clinical testing | This missense variant replaces tyrosine with cysteine at codon 61 of the PMS2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250446 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. |
| Gene |
RCV003238782 | SCV003936333 | uncertain significance | not provided | 2023-06-27 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individual(s) with colorectal cancer (Yehia et al., 2018; Lee et al., 2020); This variant is associated with the following publications: (PMID: 29684080, 32459922, 11574484) |
| Baylor Genetics | RCV003465281 | SCV004205409 | uncertain significance | Lynch syndrome 4 | 2023-10-05 | criteria provided, single submitter | clinical testing |