ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2785C>T (p.Arg929Ter)

gnomAD frequency: 0.00011  dbSNP: rs551060742
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000708848 SCV000107577 uncertain significance Lynch syndrome 2019-06-21 reviewed by expert panel curation Nonsense variant after codon 888 in MSH2 = VUS
Invitae RCV001081865 SCV000166279 benign Hereditary nonpolyposis colorectal neoplasms 2024-02-01 criteria provided, single submitter clinical testing
GeneDx RCV000586820 SCV000292728 uncertain significance not provided 2023-04-04 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation as the last 6 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Occurred in cis with a nonsense variant in the MSH6 gene in eight unrelated Portuguese Lynch syndrome families; tumor immunohistochemistry (IHC) revealed normal MSH2 expression in 5/8 cases and absence of MSH6 protein in 7/7 cases with interpretable data (Pinto et al., 2016); Observed in two individuals with colorectal cancer, co-occurring with a pathogenic MSH2 founder pathogenic variant in one individual, as well as in individuals with breast and/or ovarian cancer (Parc et al., 2003; Valentin et al., 2011; Pennington et al., 2014; Lin et al., 2016; Feliubadal et al., 2017; Sun et al., 2017); This variant is associated with the following publications: (PMID: 12624141, 28127413, 28724667, 21681552, 24344984, 24240112, 26824983, 28874130, 28332257, 29752822, 29506494, 28050010, 9774676, 18822302, 21120944, 27873144, 33015532, 31569399, 26689913, 32029870, 31207149, 26446363, 35264596)
Counsyl RCV000410460 SCV000489175 uncertain significance Lynch syndrome 1 2016-08-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000487485 SCV000574719 likely benign Hereditary cancer-predisposing syndrome 2021-01-14 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586820 SCV000601470 likely benign not provided 2020-04-06 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000487485 SCV000685073 likely benign Hereditary cancer-predisposing syndrome 2020-05-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002281911 SCV000696256 likely benign not specified 2023-12-18 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2785C>T (p.Arg929X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. This variant leads to encoding a protein that is 6 AA shorter and without interruption of any known functional domain (Pinto_MSH2_JHG_2016). Truncations downstream of this position have not been classified as pathogenic by our laboratory or in ClinVar. The variant allele was found at a frequency of 8.4e-05 in 248768 control chromosomes, predominantly at a frequency of 0.00093 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.64 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2785C>T has been reported in the literature in individuals affected with colorectal cancer, lynch syndrome, breast cancer, and prostate cancer (examples: Parc_2003, Valentin_2011, Feliubadalo_2017, Lin_2016, Pennington_2013, Pinto_2016, Lu_2015, Sun_2017, Li_2019, Kwong_2020, Fang_2023). However, many of these cases had one or more co-occurrences with other pathogenic variants (MSH2 c. 942+3A>T; MSH6 c.1030C>T, p.Gln344Ter; BRCA1 c.190T>C, p.C64R; BRCA2 c.9090dupA, p.T3030fs; BRCA1 c.4327C>T, p.R1443X) (Valentin_2011, Pinto_2016, Sun2017 and Li_2019 ), providing supporting evidence for a benign role. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. The following publications have been ascertained in the context of this evaluation (PMID: 16451135, 28127413, 24344984, 36522531, 28050010, 32068069, 29752822, 26824983, 26689913, 12624141, 24240112, 26446363, 28724667, 21681552). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments - pathogenic (n=1), likely benign/benign (n=4) and VUS (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000708848 SCV000837860 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000410460 SCV001135765 uncertain significance Lynch syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000487485 SCV002534503 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-28 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000236645 SCV000592556 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The p.Arg989X variant was identified in 10 of 474 proband chromosomes (frequency: 0.021) from South American and Portugese individuals or families with Lynch syndrome, meeting Amsterdam or Bethesda criteria, and was not identified in 200 control chromosomes from healthy individuals (Valentin 2011, Pinto 2015). However eight of the nine patients identified by Pinto et al. were also found to have a co-occurring pathogenic MSH6 mutation (c.1030C>T, p.Gln344X), five of the eight double mutant tumors had normal MSH2 expression and the ninth patient lacked a family history of colon cancer. The patient identified by Valentin et al. was also found to have a co-occurring pathogenic mutation, MSH2: c.942+3A>T (Valentin 2011). The variant was also identified in dbSNP (ID: rs551060742) “With pathogenic allele”, 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 9 of 113840 chromosomes (frequency: 0.00008) (or 9 individuals from a population of 8454 East Asian individuals, frequency 0.001); Clinvitae database (classification pathogenic), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic, and reviewed by an expert panel; being classified as pathogenic by InSight, and uncertain significance by Invitae), and UMD (9x with a “causal” classification). The above classifications were only updated as recently as 2014. The variant was also identified by our laboratory in 1 individual of Portugese background, with colon cancer, co-occurring with a pathogenic MSH6 mutation (c.1030C>T, p.Gln344X), as seen in the Portugese families from Pinto’s study (Pinto_2015_26446363). The p.Arg989X variant leads to a premature stop codon at position 989, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. However, the p.Arg989X encodes a protein 6 amino acids short of the wildtype transcript, without interruption of any known functional domain. Notably, this mutation occurs in the last exon of the MSH2 gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. However, due to conflicting interpretations above, this variant is classified as a variant of unknown significance.
Laboratory for Genotyping Development, RIKEN RCV003162498 SCV002758057 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research

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