ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3233T>C (p.Val1078Ala) (rs376452612)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000200854 SCV000254308 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1078 of the MSH6 protein (p.Val1078Ala). The valine residue is weakly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs376452612, ExAC 0.01%). This variant has been observed in an individual with pancreatic cancer (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 134855). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), as well as an algorithm developed specifically for MSH6 (PMID: 23621914), all suggest that this variant is likely to be tolerated. The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional 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.
Ambry Genetics RCV000214188 SCV000273366 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000590417 SCV000568925 uncertain significance not provided 2018-03-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3233T>C at the cDNA level, p.Val1078Ala (V1078A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). This variant was observed in 2/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old, thus the unaffected status of these individuals may not be significant. MSH6 Val1078Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Val1078Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121586 SCV000601564 uncertain significance not specified 2016-11-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590417 SCV000695846 uncertain significance not provided 2016-12-12 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3233T>C (p.Val1078Ala) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant was found in 6/122698 control chromosomes at a frequency of 0.0000489, 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, nor evaluated for functional impact by in vivo/vitro studies. Therefore, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000663151 SCV000786303 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-04-12 criteria provided, single submitter clinical testing
Color RCV000214188 SCV000903145 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing
ITMI RCV000121586 SCV000085782 not provided not specified 2013-09-19 no assertion provided reference population

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