Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000486053 | SCV000570312 | uncertain significance | not provided | 2016-05-11 | criteria provided, single submitter | clinical testing | This variant is denoted MSH6 c.3543C>G at the cDNA level, p.Asp1181Glu (D1181E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAG). This variant was observed in an individual present in the Danish HNPCC registry affected with glioblastoma. He also carried an MSH6 canonical splice site variant; however, it is unknown if the two MSH6 variants were found on the same or opposite chromosomes (in cis or trans) (Nilbert 2009, Okkels 2012, Therkildsen 2015). MSH6 Asp1181Glu was not observed in approximately 6,500 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 Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. MSH6 Asp1181Glu occurs at a position that is conserved across species and is located within domain V of the MutS domain (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Asp1181Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Invitae | RCV000556518 | SCV000624879 | uncertain significance | Hereditary nonpolyposis colon cancer | 2018-11-13 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid with glutamic acid at codon 1181 of the MSH6 protein (p.Asp1181Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs267608100, ExAC 0.02%). This variant has been reported in individuals affected with Lynch syndrome (PMID: 22495361, 18566915, 25648859). However, it occurs with a likely pathogenic variant in MSH6 in several individuals (PMID: 22495361, 25648859). While it is unknown if these variants are on the same or opposite chromosomes, these observations suggests that the c.3543C>G variant is not a primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 89409). 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, However, algorithms developed specifically for the MSH6 gene (PMID: 23621914, 2633163), do not agree on the potential impact of the missense change, 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. |
| Ambry Genetics | RCV000565574 | SCV000662391 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-08-29 | criteria provided, single submitter | clinical testing | Lines of evidence used in support of classification: Insufficient evidence |
| Counsyl | RCV000662821 | SCV000785664 | uncertain significance | Hereditary nonpolyposis colorectal cancer type 5 | 2017-10-24 | criteria provided, single submitter | clinical testing |