Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000570856 | SCV000669911 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-02-27 | criteria provided, single submitter | clinical testing | The p.I425V variant (also known as c.1273A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1273. The isoleucine at codon 425 is replaced by valine, an amino acid with highly similar properties. This alteration was detected in a family meeting Amsterdam I criteria for Lynch syndrome, however immunohistochemistry (IHC) analysis of the tumor from the individual found to carry this alteration showed intact MSH6 and absent MLH1 protein expression (Casey G et al. JAMA, 2005 Feb;293:799-809). This variant has also been identified in a cohort of 8085 Chinese breast cancer patients (Hu L et al. NPJ Breast Cancer, 2022 Apr;8:52). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV000570856 | SCV000905833 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-04 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 425 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family meeting Amsterdam I criteria for Lynch syndrome, but immunohistochemistry analysis of a carrier individual's tumor showed intact MSH6 protein expression and absent MLH1 protein expression (PMID: 15713769). This variant has been identified in 3/251344 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. |
| Invitae | RCV001063935 | SCV001228805 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2024-01-03 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003466932 | SCV004195648 | uncertain significance | Endometrial carcinoma | 2023-07-22 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV003997064 | SCV004841206 | uncertain significance | Lynch syndrome | 2023-11-30 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 425 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family meeting Amsterdam I criteria for Lynch syndrome, but immunohistochemistry analysis of a carrier individual's tumor showed intact MSH6 protein expression and absent MLH1 protein expression (PMID: 15713769). This variant has been identified in 3/251344 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. |