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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