Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001011654 | SCV001172001 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-05-21 | criteria provided, single submitter | clinical testing | The p.E484K pathogenic mutation (also known as c.1450G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1450. The glutamic acid at codon 484 is replaced by lysine, an amino acid with similar properties. This variant has been reported in an individual with MSI-H colorectal cancer that showed loss of MSH6 protein by immunohistochemistry; this individual also met Amsterdam criteria for Lynch syndrome (Dámaso E et al. Cancers (Basel), 2020 Jul;12:). Based on internal structural analysis, this variant is deleterious, is moderately destabilizing to the local structure, and is more destabilizing than nearby likely pathogenic variants (Ambry internal data). Another variant at the same codon, p.E484Q (c.1450G>C), has been identified in trans with another pathogenic MSH6 mutation in an individual with clinical features of CMMRD (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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV001340457 | SCV001534266 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-10-05 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 484 of the MSH6 protein (p.Glu484Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 32635641; Invitae). ClinVar contains an entry for this variant (Variation ID: 216297). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). This variant disrupts the p.Glu484 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been observed in individuals with MSH6-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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. |
| All of Us Research Program, |
RCV003996994 | SCV004843610 | uncertain significance | Lynch syndrome | 2023-06-26 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with lysine at codon 484 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer that exhibited microsatellite instability and loss of MSH6 protein by immunohistochemistry analysis (PMID: 32635641). 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. |
| NHS Central & South Genomic Laboratory Hub | RCV004782308 | SCV005393935 | likely pathogenic | Inherited ovarian cancer (without breast cancer) | 2024-11-11 | criteria provided, single submitter | clinical testing |