ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.942C>G (p.Ser314Arg) (rs150440246)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219163 SCV000273064 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000475100 SCV000551219 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 314 of the MSH6 protein (p.Ser314Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs150440246, ExAC 0.07%). This variant has been reported in individuals affected with endometrial cancer (PMID: 27443514) and colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 229741). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies and their 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 RCV000478810 SCV000569371 uncertain significance not provided 2017-10-23 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.942C>G at the cDNA level, p.Ser314Arg (S314R) at the protein level, and results in the change of a Serine to an Arginine (AGC>AGG). This variant was observed in an individual with endometrial cancer (Ring 2016). MSH6 Ser314Arg was observed at an allele frequency of 0.05% (12/24018) in individuals of African ancestry in large population cohorts (Lek 2016). Since Serine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Ser314Arg occurs at a position that is not conserved and is located in the nuclear localization signal (Gassman 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Ser314Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659889 SCV000781785 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000219163 SCV000911372 likely benign Hereditary cancer-predisposing syndrome 2016-04-11 criteria provided, single submitter clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761132 SCV000891048 uncertain significance Hepatoblastoma 2016-12-05 no assertion criteria provided clinical testing

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