Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000166714 | SCV000217524 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-10 | criteria provided, single submitter | clinical testing | The p.I622L variant (also known as c.1864A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 1864. The isoleucine at codon 622 is replaced by leucine, an amino acid with highly similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE, 2014 Apr;9:e94554). This amino acid position is poorly conserved in available vertebrate species. 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. |
Color Diagnostics, |
RCV000166714 | SCV000908383 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-06 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with leucine at codon 622 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 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. |
Invitae | RCV000791828 | SCV000931092 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-10-01 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 622 of the MSH6 protein (p.Ile622Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 134849). 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. 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. |
Institute for Biomarker Research, |
RCV000166714 | SCV004228174 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-31 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV003997352 | SCV004835467 | uncertain significance | Lynch syndrome | 2023-10-27 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with leucine at codon 622 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 been reported in an individual affected with Lynch syndrome but co-occurring with a likely pathogenic MLH1 variant (Universal Mutation Database: www.umd.be). 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. |
ITMI | RCV000121572 | SCV000085768 | not provided | not specified | 2013-09-19 | no assertion provided | reference population |