ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2648A>C (p.Lys883Thr)

gnomAD frequency: 0.00001  dbSNP: rs764816440
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484043 SCV000570140 uncertain significance not provided 2016-04-26 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2648A>C at the cDNA level, p.Lys883Thr (K883T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Lys883Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Lys883Thr occurs at a position that is not conserved and is located in the MutS domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Lys883Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000553546 SCV000624781 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV001016203 SCV001177127 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-23 criteria provided, single submitter clinical testing The p.K883T variant (also known as c.2648A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 2648. The lysine at codon 883 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well 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, LLC DBA Color Health RCV001016203 SCV001344435 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-13 criteria provided, single submitter clinical testing This missense variant replaces lysine with threonine at codon 883 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 been identified in 3/250492 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 RCV000484043 SCV002774640 uncertain significance not provided 2021-07-06 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004003343 SCV004838382 uncertain significance Lynch syndrome 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces lysine with threonine at codon 883 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 been identified in 3/250492 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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