ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.727C>T (p.Arg243Cys) (rs377216828)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132028 SCV000187087 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000410426 SCV000487921 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-01 criteria provided, single submitter clinical testing
Invitae RCV000464603 SCV000551083 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 243 of the MSH6 protein (p.Arg243Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs377216828, ExAC 0.002%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 142675). An algorithm developed specifically for the MSH6 gene (PMID: 23621914) suggests that this missense change is likely to be tolerated. However, this prediction has not been confirmed by published functional studies and the 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.
GeneDx RCV000480539 SCV000567222 uncertain significance not provided 2016-08-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.727C>T at the cDNA level, p.Arg243Cys (R243C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Arg243Cys was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg243Cys occurs at a position that is not conserved and is not located in a known functional domain (Kariola 2002, Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available information, it is unclear whether MSH6 Arg243Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000132028 SCV000908357 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-03 criteria provided, single submitter clinical testing

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