Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000132161 | SCV000187236 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-02-14 | criteria provided, single submitter | clinical testing | The p.E484Q pathogenic mutation (also known as c.1450G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 1450. The glutamic acid at codon 484 is replaced by glutamine, an amino acid with highly similar properties. This variant has been identified in trans with another pathogenic MSH6 mutation in an individual with clinical features of CMMRD (Ambry internal data). This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated loss of MSH6 expression by immunohistochemistry (Ambry internal data, external communication). Interrogation of the local protein structure indicates that this substitution would be destabilizing (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV000203804 | SCV000260923 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2024-01-31 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 484 of the MSH6 protein (p.Glu484Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 142768). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Gene |
RCV000480825 | SCV000565994 | uncertain significance | not provided | 2023-10-09 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as germline pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19584161, 23621914, 17531815, 21120944) |
| All of Us Research Program, |
RCV003998134 | SCV004830285 | uncertain significance | Lynch syndrome | 2023-06-28 | criteria provided, single submitter | clinical testing |