Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000230740 | SCV000283786 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2020-03-25 | criteria provided, single submitter | clinical testing | 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. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 237180). This variant is present in population databases (rs759260316, ExAC 0.001%). This sequence change replaces asparagine with lysine at codon 1065 of the MSH6 protein (p.Asn1065Lys). The asparagine residue is weakly conserved and there is a moderate physicochemical difference between asparagine and lysine. |
Ambry Genetics | RCV002321850 | SCV002609424 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-19 | criteria provided, single submitter | clinical testing | The p.N1065K variant (also known as c.3195C>G), located in coding exon 5 of the MSH6 gene, results from a C to G substitution at nucleotide position 3195. The asparagine at codon 1065 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. 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. |
All of Us Research Program, |
RCV003998726 | SCV004817404 | uncertain significance | Lynch syndrome | 2023-09-17 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with lysine at codon 1065 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/251354 chromosomes 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. |