ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.893G>A (p.Arg298Gln) (rs765237563)

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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 RCV000165781 SCV000216526 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000168235 SCV000218904 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 298 of the MSH6 protein (p.Arg298Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs765237563, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 186227). 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 RCV000588989 SCV000279371 uncertain significance not provided 2016-03-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.893G>A at the cDNA level, p.Arg298Gln (R298Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Arg298Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Arg298Gln occurs at a position that is not conserved and is not located in a known functional domain (Kariola 2002,Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Arg298Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000165781 SCV000685527 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588989 SCV000695931 uncertain significance not provided 2017-05-08 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.893G>A (p.Arg298Gln) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 2/121148 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
GeneKor MSA RCV000165781 SCV000822071 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000758602 SCV000887356 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.893G>A has a 14.6% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.

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