ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1814C>G (p.Thr605Ser) (rs587781616)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129705 SCV000184506 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000587763 SCV000211349 uncertain significance not provided 2018-11-12 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1814C>G at the cDNA level, p.Thr605Ser (T605S) at the protein level, and results in the change of a Threonine to a Serine (ACT>AGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Thr605Ser was observed at an allele frequency of 0.01% (13/126,470) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the surface loop of the connector domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Thr605Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000200701 SCV000254282 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 605 of the MSH6 protein (p.Thr605Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs587781616, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 141265). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000129705 SCV000685228 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587763 SCV000695796 uncertain significance not provided 2017-08-08 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1814C>G (p.Thr605Ser) variant located in the DNA mismatch repair protein MutS, connector domain (via InterPro) involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 15/276888 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000103 (13/126470). This frequency is comparable to the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this variant could be a rare benign polymorphism found in population(s) of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Although, multiple clinical diagnostic laboratories and a reputable database classified this variant as uncertain significance. 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 RCV000129705 SCV000822061 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000708871 SCV000837888 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587763 SCV000889461 uncertain significance not provided 2018-03-29 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765684 SCV000897026 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing

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