ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3796C>T (p.His1266Tyr)

gnomAD frequency: 0.00001  dbSNP: rs972387746
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548179 SCV000624919 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-08-02 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 455286). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1266 of the MSH6 protein (p.His1266Tyr).
Ambry Genetics RCV001021161 SCV001182740 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-01 criteria provided, single submitter clinical testing The p.H1266Y variant (also known as c.3796C>T), located in coding exon 8 of the MSH6 gene, results from a C to T substitution at nucleotide position 3796. The histidine at codon 1266 is replaced by tyrosine, an amino acid with similar properties. 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.
Color Diagnostics, LLC DBA Color Health RCV001021161 SCV002052188 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-17 criteria provided, single submitter clinical testing This missense variant replaces histidine with tyrosine at codon 1266 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 MSH6-related disorders in the literature. This variant has been identified in 2/251216 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.
Sema4, Sema4 RCV001021161 SCV002528067 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-26 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV004003698 SCV004835141 uncertain significance Lynch syndrome 2023-06-28 criteria provided, single submitter clinical testing This missense variant replaces histidine with tyrosine at codon 1266 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 MSH6-related disorders in the literature. This variant has been identified in 2/251216 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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