ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.751A>G (p.Ile251Val) (rs554884560)

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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 RCV000215096 SCV000277875 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000220612 SCV000279608 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.751A>G at the cDNA level, p.Ile251Val (I251V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant was observed in one hereditary breast and colon cancer family (1/68) and absent in 166 healthy controls (Wasielewski 2010). MSH6 Ile251Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ile251Val occurs at a position that is not conserved and is located in the nuclear localization signals domain (Gassman 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Ile251Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000630227 SCV000751183 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 251 of the MSH6 protein (p.Ile251Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family affected with hereditary breast and colorectal cancer (PMID: 19924528) and in an individual with colorectal cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89564). Two algorithms developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914, 22290698). 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 RCV000662409 SCV000784839 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-01-04 criteria provided, single submitter clinical testing
Color RCV000215096 SCV000911421 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-16 criteria provided, single submitter clinical testing

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