ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2664G>C (p.Lys888Asn) (rs730881798)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759138 SCV000211300 uncertain significance not provided 2017-05-30 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2664G>C at the cDNA level, p.Lys888Asn (K888N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Lys888Asn was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Lys888Asn occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located within the Lever domain (Warren 2007, Kansikas 2011). 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 Lys888Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160683 SCV000213658 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000205971 SCV000261292 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 888 of the MSH6 protein (p.Lys888Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs730881798, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182637). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV000160683 SCV000685306 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759138 SCV000888264 uncertain significance not provided 2017-09-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781587 SCV000919752 uncertain significance not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2664G>C (p.Lys888Asn) results in a non-conservative amino acid change located in the DNA mismatch repair ATPase MutS domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 245364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2664G>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV001142302 SCV001302727 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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