Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000204112 | SCV000259522 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2019-11-12 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with arginine at codon 46 of the MSH6 protein (p.Gly46Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 22495361). ClinVar contains an entry for this variant (Variation ID: 219577). 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 arginine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 |
RCV000484712 | SCV000566519 | uncertain significance | not provided | 2016-12-07 | criteria provided, single submitter | clinical testing | This variant is denoted MSH6 c.136G>A at the cDNA level, p.Gly46Arg (G46R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant was observed in at least one individual diagnosed with colon cancer with normal immunohistochemistry staining (Okkels 2012). MSH6 Gly46Arg was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Gly46Arg occurs at a position that is not conserved and is not located in a known functional domain (Kariola 2002, Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Gly46Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Ambry Genetics | RCV000561391 | SCV000662356 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-09-17 | criteria provided, single submitter | clinical testing | Insufficient evidence |
| Counsyl | RCV000663157 | SCV000786312 | uncertain significance | Hereditary nonpolyposis colorectal cancer type 5 | 2018-04-06 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV000765676 | SCV000897018 | uncertain significance | Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Color | RCV000561391 | SCV000911817 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-01-17 | criteria provided, single submitter | clinical testing |