Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000474226 | SCV000551247 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-10-07 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1036 of the MSH6 protein (p.Leu1036Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 410507). 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. 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 |
RCV001753898 | SCV002005134 | uncertain significance | not provided | 2023-02-15 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals diagnosed with colon cancer, one of which also was found to have a pathogenic MLH1 variant (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 17531815, 21120944, 28135145) |
All of Us Research Program, |
RCV004001850 | SCV004824777 | uncertain significance | Lynch syndrome | 2024-01-11 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with arginine at codon 1036 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145), however, one of these individuals also carried a pathogenic variant in MLH1 gene that could explain the observed phenotype. This variant has not been identified 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. |