Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000204386 | SCV000259977 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2019-04-08 | criteria provided, single submitter | clinical testing | This sequence change replaces proline with serine at codon 85 of the MSH6 protein (p.Pro85Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. While this variant is present in population databases (rs779664343), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 219868). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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. |
| Gene |
RCV000482986 | SCV000565906 | uncertain significance | not provided | 2015-03-17 | criteria provided, single submitter | clinical testing | This variant is denoted MSH6 c.253C>T at the cDNA level, p.Pro85Ser (P85S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Pro85Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Pro85Ser occurs at a position that is not conserved across species and is not located in a known functional domain (Terui 2013, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH6 Pro85Ser is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Ambry Genetics | RCV000575872 | SCV000669983 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-08-25 | criteria provided, single submitter | clinical testing | The p.P85S variant (also known as c.253C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 253. The proline at codon 85 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. 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. |
| Mendelics | RCV000986699 | SCV001135779 | uncertain significance | Hereditary nonpolyposis colorectal cancer type 5 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Color | RCV000575872 | SCV001352501 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-08-15 | criteria provided, single submitter | clinical testing |