ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1403G>C (p.Arg468Pro)

gnomAD frequency: 0.00003  dbSNP: rs41295268
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223504 SCV000277645 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-16 criteria provided, single submitter clinical testing The p.R468P variant (also known as c.1403G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 1403. The arginine at codon 468 is replaced by proline, an amino acid with dissimilar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-1389). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000456959 SCV000551225 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-30 criteria provided, single submitter clinical testing
GeneDx RCV000486815 SCV000571091 uncertain significance not provided 2023-03-10 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; Identified in an individual with endometrial cancer in published literature (Ring et al., 2016); This variant is associated with the following publications: (PMID: 21060849, 15470502, 28922847, 17531815, 21120944, 27443514, 30798936)
Color Diagnostics, LLC DBA Color Health RCV000223504 SCV000690198 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-21 criteria provided, single submitter clinical testing This missense variant replaces arginine with proline at codon 468 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 an individual affected with endometrial cancer (PMID: 27443514). This variant has been identified in 2/282540 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486815 SCV001134394 uncertain significance not provided 2019-03-12 criteria provided, single submitter clinical testing
Baylor Genetics RCV003469073 SCV004195666 uncertain significance Endometrial carcinoma 2023-07-13 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003998047 SCV004841361 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces arginine with proline at codon 468 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). This variant has also been identified in 2/282540 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.

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