ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.854G>T (p.Ser285Ile) (rs63750878)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212635 SCV000211264 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.854G>T at the cDNA level, p.Ser285Ile (S285I) at the protein level, and results in the change of a Serine to an Isoleucine (AGT>ATT). This variant was observed in an individual with a personal history of a MSI-L colon cancer and a family history of colon, breast and ovarian cancer (Kolodner 1999). Functional assays have had disparate results, showing that MSH6 Ser285Ile does not affect nuclear transport of MSH6 nor ATP hydrolysis and is not resistant to DNA damaging agents, but does exhibit a decreased ability to bind ATP and alters subcellular localization (Cyr 2008, Gassman 2011, Belvederesi 2012, Houlleberghs 2017). MSH6 Ser285Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser285Ile is located in the nuclear localization signals (Gassman 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Ser285Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160657 SCV000214780 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Intact protein function observed in appropriate functional assay(s)
Invitae RCV000556949 SCV000625012 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 285 of the MSH6 protein (p.Ser285Ile). The serine residue is weakly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs63750878, ExAC 0.002%). This variant has been reported in an individual affected with colorectal cancer (PMID: 10537275), and a family affected with Lynch syndrome (PMID: 18790734). ClinVar contains an entry for this variant (Variation ID: 89571). Experimental studies demonstrate that this missense change results in normal MSH2 binding, modestly reduced ATPase activity, and does not appear to affect DNA mismatch repair (MMR) activity (PMID: 18790734, 28531214). This variant may affect nuclear localization of MSH6, but results from in vitro studies are conflicting (PMID: 22851212, 21437237). 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 RCV000160657 SCV000690483 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001174593 SCV001337785 uncertain significance not specified 2020-01-17 criteria provided, single submitter clinical testing Variant summary: MSH6 c.854G>T (p.Ser285Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251154 control chromosomes (gnomAD). c.854G>T has been reported in the literature in at least one individual affected with familial colorectal cancer (Kolodner_1999). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Several publications report experimental evidence evaluating an impact on protein function, with conflicting results. The variant protein demonstrated modestly reduced ATPase activity, but does not appear to to alter DNA binding or DNA mismatch repair (e.g. Cyr_2008, Houlleberghs_2017). Studies assessing an impact on nuclear localization are conflicting (e.g. Gassman_2011, Belvederesi_2012). Evaluation of CRC tumor tissue from a patient with the variant showed loss of heterozygosity of the wild-type allele, but only low levels of microsatellite instability (Kolodner_1999). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
CSER _CC_NCGL, University of Washington RCV000148648 SCV000190363 uncertain significance Colorectal cancer 2014-06-01 no assertion criteria provided research

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.