ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3772C>G (p.Gln1258Glu) (rs63750554)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227470 SCV000283822 uncertain significance Hereditary nonpolyposis colon cancer 2018-05-21 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 1258 of the MSH6 protein (p.Gln1258Glu). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs63750554, ExAC 0.07%). This variant has been observed in individuals with suspected Lynch syndrome, one of whom was also reported to carry an unspecified pathogenic variant (PMID: 29575718, 28874130). ClinVar contains an entry for this variant (Variation ID: 237198). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000766490 SCV000569546 uncertain significance not provided 2016-09-12 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3772C>G at the cDNA level, p.Gln1258Glu (Q1258E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gln1258Glu was not observed at significant allele frequency in the NHLBI Exome Sequencing Project or 1000 Genomes. Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Gln1258Glu occurs at a position that is not conserved and is located within the MutS domain V (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Gln1258Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491197 SCV000580142 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479785 SCV000601585 uncertain significance not specified 2016-10-06 criteria provided, single submitter clinical testing
Color RCV000491197 SCV000905458 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-21 criteria provided, single submitter clinical testing

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