Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000129553 | SCV000184333 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-30 | criteria provided, single submitter | clinical testing | The p.T165I variant (also known as c.494C>T), located in coding exon 5 of the PMS2 gene, results from a C to T substitution at nucleotide position 494. The threonine at codon 165 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is well 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. |
| Invitae | RCV000696062 | SCV000824609 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-14 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 165 of the PMS2 protein (p.Thr165Ile). This variant is present in population databases (rs587781541, gnomAD no frequency). This missense change has been observed in individual(s) with PMS2-related conditions (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 141163). 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 expected to disrupt PMS2 protein function with a positive 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. |
| Fulgent Genetics, |
RCV000765967 | SCV000897388 | uncertain significance | Mismatch repair cancer syndrome 1; Lynch syndrome 4 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000129553 | SCV001360035 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-02 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with isoleucine at codon 165 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 1/250360 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 |
RCV001753510 | SCV002005487 | uncertain significance | not provided | 2019-10-10 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
| Baylor Genetics | RCV003460895 | SCV004207793 | uncertain significance | Lynch syndrome 4 | 2023-07-12 | criteria provided, single submitter | clinical testing |