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

dbSNP: rs777054839

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000794026	SCV000933409	pathogenic	not provided	2024-01-04	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. Loss-of-function variants in MSH3 are known to be pathogenic (PMID: 27476653, 37402566). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 28944238). ClinVar contains an entry for this variant (Variation ID: 640896). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001016296	SCV001177236	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-08	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	RCV000794026	SCV001477673	likely pathogenic	not 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000794026	SCV002010456	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003458518	SCV004189054	pathogenic	Familial adenomatous polyposis 4	2023-08-31	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV003461079	SCV004197075	likely pathogenic	Endometrial carcinoma	2024-03-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000794026	SCV004221081	pathogenic	not provided	2023-04-26	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MSH3 protein synthesis. The frequency of this variant in the general population, 0.000046 (6/129144 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 28944238 (2017)), endometrial cancer (PMID: 34994648 (2021)), and breast cancer (PMID: 34250384 (2021)). Based on the available information, this variant is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004751705	SCV005366070	pathogenic	MSH3-related disorder	2024-05-31	no assertion criteria provided	clinical testing	The MSH3 c.2686G>T variant is predicted to result in premature protein termination (p.Gly896*). This variant has been reported in individuals with colorectal, endometrial, or breast cancer (DeRycke et al 2017. PubMed ID: 28944238; Adam R et al 2016. PubMed ID: 27476653; Villy MC et al 2023. PubMed ID: 37402566; Levine MD et al 2021. PubMed ID: 34994648; Salo-Mullen EE et al 2021. PubMed ID: 34250384). This variant is reported in 0.0046% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic/likely pathogenic by multiple submitters in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/640896/). Nonsense variants in MSH3 are expected to be pathogenic. This variant is interpreted as pathogenic.