Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001049290 | SCV001213335 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2020-03-18 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glutamine at codon 78 of the PMS2 protein (p.Glu78Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant has not been reported in the literature in individuals with PMS2-related conditions. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. |
| Ambry Genetics | RCV002445258 | SCV002732487 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-13 | criteria provided, single submitter | clinical testing | The p.E78Q variant (also known as c.232G>C), located in coding exon 3 of the PMS2 gene, results from a G to C substitution at nucleotide position 232. The glutamic acid at codon 78 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. 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. |
| Neuberg Supratech Reference Laboratories Pvt Ltd, |
RCV003388601 | SCV004100596 | uncertain significance | Lynch syndrome 4 | criteria provided, single submitter | clinical testing | The missense variant p.E78Q in PMS2 (NM_000535.7) is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between glutamic acid and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.E78Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.232 in PMS2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. |