Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000166983 | SCV000217804 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-22 | criteria provided, single submitter | clinical testing | The p.K295I variant (also known as c.884A>T), located in coding exon 4 of the MSH6 gene, results from an A to T substitution at nucleotide position 884. The lysine at codon 295 is replaced by isoleucine, an amino acid with dissimilar properties. This variant was detected in a study of 1046 familial colorectal cancer cases and 1006 unrelated controls (Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). This variant has also been identified in probands whose Lynch syndrome-associated tumors demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC) (Ambry internal data; Shirts BH et al. Genet Med, 2016 10;18:974-81). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
University of Washington Department of Laboratory Medicine, |
RCV000210183 | SCV000266214 | uncertain significance | Lynch syndrome | 2015-11-20 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000166983 | SCV000690487 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-08-30 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000693641 | SCV000821517 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-04 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 295 of the MSH6 protein (p.Lys295Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biliary tract cancer and/or colorectal cancer (PMID: 26845104, 29212164, 36243179). ClinVar contains an entry for this variant (Variation ID: 187266). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. 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 |
RCV001778764 | SCV002015258 | uncertain significance | not provided | 2021-05-11 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colorectal cancer (Raskin 2017); This variant is associated with the following publications: (PMID: 29212164) |