Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000165918 | SCV000216673 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-07 | criteria provided, single submitter | clinical testing | The c.1231_1232delGAinsTT variant, located in coding exon 11 of the PMS2 gene, results from an in-frame deletion of GA and insertion of TT at nucleotide positions 1231 to 1232. This results in the substitution of the glutamic acid residue for a leucine residue at codon 411, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV000481458 | SCV000571404 | uncertain significance | not specified | 2016-08-18 | criteria provided, single submitter | clinical testing | This variant is denoted PMS2 c.1231_1232delGAinsTT at the cDNA level and p.Glu411Leu (E411L) at the protein level. The normal sequence, with the bases that are deleted in braces and inserted in brackets is AGAA[delGA][insTT]AAAAAAAG. This in frame deletion and insertion occurs on the same allele (in cis) and results in the missense change of a Glutamic acid to a Leucine (GAA>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Neither PMS2 c.1231_1232delGAinsTT nor Glu411Leu (by this or an alternate nucleotide change) was observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic acid and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Glu411Leu occurs at a position that is not conserved and is not located in a known functional domain (Uniprot). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Glu411Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Invitae | RCV000694340 | SCV000822780 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-11-06 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with leucine, which is neutral and non-polar, at codon 411 of the PMS2 protein (p.Glu411Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 186339). 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 tolerated. 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. |