Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000563874 | SCV000664963 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-15 | criteria provided, single submitter | clinical testing | The p.T84P variant (also known as c.250A>C), located in coding exon 3 of the PMS2 gene, results from an A to C substitution at nucleotide position 250. The amino acid change results in threonine to proline at codon 84, an amino acid with highly similar properties. This nucleotide position and amino acid position are not well conserved in available vertebrate species. This change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing; however, RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This variant was reported in a cohort of Moroccan triple negative breast cancer patients (Laraqui A et al. J Genomics, 2021 Sep;9:43-54). 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 | RCV001055075 | SCV001219440 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-31 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 84 of the PMS2 protein (p.Thr84Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34646395). ClinVar contains an entry for this variant (Variation ID: 480955). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |
| Sema4, |
RCV000563874 | SCV002530312 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-26 | criteria provided, single submitter | curation | |
| Baylor Genetics | RCV003465184 | SCV004207844 | uncertain significance | Lynch syndrome 4 | 2023-05-11 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV004000909 | SCV004842137 | uncertain significance | Lynch syndrome | 2023-05-04 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with proline at codon 84 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 been reported in a cohort of individuals affected with triple negative breast cancer (PMID: 34646395). This variant has not been identified 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. |