ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2258C>G (p.Ser753Cys)

gnomAD frequency: 0.00002  dbSNP: rs876660934
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219984 SCV000278752 uncertain significance Hereditary cancer-predisposing syndrome 2024-12-02 criteria provided, single submitter clinical testing The p.S753C variant (also known as c.2258C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2258. The serine at codon 753 is replaced by cysteine, an amino acid with dissimilar 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000473229 SCV000551273 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-11-21 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 753 of the MSH6 protein (p.Ser753Cys). 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: 234218). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. 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 RCV000219984 SCV000685271 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-15 criteria provided, single submitter clinical testing This missense variant replaces serine with cysteine at codon 753 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 MSH6-related disorders 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985831 SCV001134408 uncertain significance not provided 2020-01-27 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000985831 SCV001250447 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000985831 SCV001780603 uncertain significance not provided 2024-07-12 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)
Baylor Genetics RCV003463605 SCV004197594 uncertain significance Endometrial carcinoma 2024-03-06 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003998608 SCV004841905 uncertain significance Lynch syndrome 2023-04-27 criteria provided, single submitter clinical testing This missense variant replaces serine with cysteine at codon 753 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed 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.
Breakthrough Genomics, Breakthrough Genomics RCV000985831 SCV005187675 uncertain significance not provided criteria provided, single submitter not provided

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