ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1763A>G (p.His588Arg)

dbSNP: rs786202725
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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 RCV000165680 SCV000216418 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-27 criteria provided, single submitter clinical testing The p.H588R variant (also known as c.1763A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1763. The histidine at codon 588 is replaced by arginine, an amino acid with highly similar properties. This alteration is observed in an individual whose endometrial tumor was microsatellite stable and demonstrated normal mismatch repair protein expression on immunohistochemistry (IHC) (Ambry internal data). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000206412 SCV000260012 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-08 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 588 of the MSH6 protein (p.His588Arg). 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: 186142). 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.
Color Diagnostics, LLC DBA Color Health RCV000165680 SCV000685225 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-30 criteria provided, single submitter clinical testing This missense variant replaces histidine with arginine at codon 588 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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Counsyl RCV000662615 SCV000785277 uncertain significance Lynch syndrome 5 2017-06-23 criteria provided, single submitter clinical testing
GeneDx RCV001547984 SCV001767822 uncertain significance not provided 2023-09-12 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17531815, 21120944)
Myriad Genetics, Inc. RCV000662615 SCV004018941 uncertain significance Lynch syndrome 5 2023-03-28 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 RCV003462183 SCV004195740 uncertain significance Endometrial carcinoma 2023-06-07 criteria provided, single submitter clinical testing

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