Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000565281 | SCV000663458 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-09-29 | criteria provided, single submitter | clinical testing | Insufficient or conflicting evidence |
| Invitae | RCV000814744 | SCV000955166 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2018-11-20 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine with aspartic acid at codon 833 of the PMS2 protein (p.His833Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 480306). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. |