ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.753A>G (p.Ile251Met)

dbSNP: rs587779321
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506023 SCV000601618 uncertain significance not specified 2016-12-08 criteria provided, single submitter clinical testing
Invitae RCV000803732 SCV000943616 benign Hereditary nonpolyposis colorectal neoplasms 2023-11-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV001026537 SCV001188939 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-16 criteria provided, single submitter clinical testing The p.I251M variant (also known as c.753A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 753. The isoleucine at codon 251 is replaced by methionine, an amino acid with highly 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. In addition, the CoDP in silico tool predicts this alteration to have a minor impact on molecular function, with a score of 0.000 (Terui H et al. J. Biomed. Sci. 2013 Apr;20:25). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV001026537 SCV001350842 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-18 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with methionine at codon 251 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 1/251174 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.
All of Us Research Program, National Institutes of Health RCV003997103 SCV004837008 uncertain significance Lynch syndrome 2023-08-15 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with methionine at codon 251 of the MSH6 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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 been identified in 1/251174 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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