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 2020-08-05 criteria provided, single submitter clinical testing The p.S314R variant (also known as c.942C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 942. The serine at codon 314 is replaced by arginine, an amino acid with dissimilar properties. This variant has been previously detected in endometrial and colorectal cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod. Pathol., 2016 11;29:1381-1389; Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095). This variant has also been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with acute lymphoblastic leukemia (Zhang J et al. N. Engl. J. Med., 2015 Dec;373:2336-2346). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000475100 SCV000551219 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-09-18 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 likely benign not provided 2020-03-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27443514, 28135145)
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
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761132 SCV000891048 uncertain significance Lynch syndrome 2020-10-15 criteria provided, single submitter clinical testing The MSH6 c.942C>G (p.Ser314Arg) missense change has a maximum subpopulation frequency of 0.056% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48026064-C-G). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer (PMID: 28135145) and endometrial cancer (PMID: 27443514). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Color Health, Inc RCV000219163 SCV000911372 likely benign Hereditary cancer-predisposing syndrome 2016-04-11 criteria provided, single submitter clinical testing

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