ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.682G>A (p.Glu228Lys)

dbSNP: rs587779947
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115441 SCV000149350 uncertain significance not provided 2023-09-13 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a non-colorectal tumor displaying mismatch repair deficiency (Le et al., 2017); This variant is associated with the following publications: (PMID: 21437237, 28596308, 29245953)
Counsyl RCV000410116 SCV000488711 uncertain significance Lynch syndrome 5 2016-05-26 criteria provided, single submitter clinical testing
Invitae RCV000466432 SCV000551269 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000566072 SCV000662437 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-23 criteria provided, single submitter clinical testing The p.E228K variant (also known as c.682G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 682. The glutamic acid at codon 228 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000566072 SCV000690470 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-15 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 228 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 observed in an individual affected with colorectal cancer (PMID: 29245953) and another individual affected with unspecified cancer (PMID: 28596308). This variant has been identified in 1/250430 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.
Myriad Genetics, Inc. RCV000410116 SCV004018989 uncertain significance Lynch syndrome 5 2023-03-29 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics RCV003467044 SCV004195709 uncertain significance Endometrial carcinoma 2023-06-23 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003997255 SCV004836808 uncertain significance Lynch syndrome 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 228 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 observed in an individual affected with colorectal cancer (PMID: 29245953) and another individual affected with unspecified cancer that is non-colorectal (PMID: 28596308). This variant has been identified in 1/250430 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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