ClinVar Miner

Submissions for variant NM_002439.5(MSH3):c.2686G>T (p.Gly896Ter) (rs777054839)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000794026 SCV000933409 pathogenic not provided 2020-10-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly896*) in the MSH3 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs777054839, ExAC 0.001%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28944238). ClinVar contains an entry for this variant (Variation ID: 640896). Loss-of-function variants in MSH3 are known to be pathogenic (PMID: 27476653). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001016296 SCV001177236 pathogenic Hereditary cancer-predisposing syndrome 2019-11-01 criteria provided, single submitter clinical testing The p.G896* pathogenic mutation (also known as c.2686G>T), located in coding exon 20 of the MSH3 gene, results from a G to T substitution at nucleotide position 2686. This changes the amino acid from a glycine to a stop codon within coding exon 20. This alteration has been reported in a compound heterozygous state in one patient from a cohort of 1231 individuals with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289698 SCV001477673 likely pathogenic none provided 2020-01-24 criteria provided, single submitter clinical testing The MSH3 c.2686G>T; p.Gly896Ter variant (rs777054839) is reported in the literature in an individual with colorectal cancer (DeRycke 2017), and is reported in ClinVar (Variation ID: 640896). This variant is found in the general population with a low overall allele frequency of 0.002% (6/282816 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Loss-of-function variants in MSH3 are known to be pathogenic (Adam 2016). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Adam R et al. Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. Am J Hum Genet. 2016 Aug 4;99(2):337-51. DeRycke MS et al. Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. Mol Genet Genomic Med. 2017 Jul 23;5(5):553-569.

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