ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.107C>T (p.Ala36Val) (rs61756469)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128922 SCV000172791 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-18 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000220784 SCV000279090 uncertain significance not provided 2017-09-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.107C>T at the cDNA level, p.Ala36Val (A36V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). This variant has been reported in two related individuals with non-medullary thyroid carcinoma (Yu 2015). MSH6 Ala36Val was observed at an allele frequency of 0.08% (6/7,250) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ala36Val occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Ala36Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000226897 SCV000283699 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 36 of the MSH6 protein (p.Ala36Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs61756469, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a family affected with non-medullary thyroid cancer (PMID: 26530882). ClinVar contains an entry for this variant (Variation ID: 140779). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its 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.
Counsyl RCV000412094 SCV000488415 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-03-18 criteria provided, single submitter clinical testing
Color RCV000128922 SCV000685162 likely benign Hereditary cancer-predisposing syndrome 2020-02-19 criteria provided, single submitter clinical testing
Mendelics RCV000708850 SCV000837862 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000220784 SCV000889452 uncertain significance not provided 2019-01-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780475 SCV000917752 likely benign not specified 2018-03-30 criteria provided, single submitter clinical testing Variant summary: MSH6 c.107C>T (p.Ala36Val) results in a non-conservative amino acid change located outside of any known functional domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. An algorithm developed specifically to ascertain variants in MSH6 gene suggest that this missense change has no impact on MSH6 function (Terui_2013). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5.35 fold above the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The c.107C>T has been reported in the literature in two family members affected with familial non-medullary thyroid cancer without reported personal or family history of Lynch Syndrome; both individuals also carried in-frame variant in GNAS gene (Lu_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 likely benign.
Mendelics RCV000412094 SCV001135773 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.