Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000558096 | SCV000624755 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-07 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 795 of the MSH6 protein (p.Ile795Val). 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: 455195). 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. |
| Ambry Genetics | RCV001015335 | SCV001176157 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-26 | criteria provided, single submitter | clinical testing | The p.I795V variant (also known as c.2383A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2383. The isoleucine at codon 795 is replaced by valine, an amino acid with highly similar properties. This variant was observed in 1/287 patients with hereditary breast and/or ovarian cancer; this patient was diagnosed with breast cancer at age 40 and had a family history of breast cancer (Caminsky NG et al. Hum Mutat, 2016 07;37:640-52). In another study, this variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other 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, |
RCV001015335 | SCV001342493 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-13 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 795 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 breast and/or ovarian cancer (PMID: 26898890). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991). 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. |
| ARUP Laboratories, |
RCV001811026 | SCV002048060 | uncertain significance | not provided | 2021-09-13 | criteria provided, single submitter | clinical testing | The MSH6 c.2383A>G; p.Ile795Val variant (rs865931684), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 455195). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The isoleucine at codon 795 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.268). Another amino acid substitutions at this codon (p.Ile795Thr) has been reported in an individual affected with pancreatic cancer, although its clinical significance was considered uncertain (Shindo 2017). Due to limited information, the clinical significance of the p.Ile795Val variant is uncertain at this time. References: Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390. PMID: 28767289. |
| All of Us Research Program, |
RCV004003678 | SCV004834287 | uncertain significance | Lynch syndrome | 2024-01-03 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 795 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 breast and/or ovarian cancer (PMID: 26898890). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991). 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. |