ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2801C>T (p.Thr934Met) (rs587779969)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212622 SCV000149433 likely benign not provided 2021-05-04 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29596542, 31391288, 26898890, 27720647, 19117025, 27498913, 31569399)
Ambry Genetics RCV000115524 SCV000187163 likely benign Hereditary cancer-predisposing syndrome 2018-06-28 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification
Invitae RCV001086842 SCV000262352 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115524 SCV000690098 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-12 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 934 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer, ovarian cancer, gastrointestinal stromal tumor and unspecified cancer (PMID: 19117025, 26898890, 27498913, 29596542, 31391288, 31569399) with some tumors exhibiting MMR-proficient characteristics (PMID: 29596542, 31391288). This variant has been identified in 14/247562 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics RCV000986691 SCV001135766 likely benign Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194031 SCV001363267 uncertain significance not specified 2019-10-10 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2801C>T (p.Thr934Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 247562 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (5.7e-05 vs 0.00057), allowing no conclusion about variant significance. c.2801C>T has been reported in the literature in individuals affected with HBOC, colorectal cancer in addition to an individual referred for genetic testing (Caminsky_2016, Hampel_2018, Mu_2016, South_2009, Wu_2019). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three classified as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357791 SCV001553372 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MSH2 p.Thr934Met variant was identified in 2 of 728 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome and ovarian cancer (Caminsky 2016, South 2009). The variant was also identified in the following databases: dbSNP (ID: rs587779969 as “With Uncertain significance allele”), ClinVar (1x as likely benign by Invitae and 3x uncertain significance by GeneDx, Ambry Genetics, and Color Genomics), UMD-LSDB (5x as neutral), Insight Colon Cancer Gene Variant Database, and Insight Hereditary Tumors Database. The variant was not identified in the COGR, Cosmic, MutDB, Zhejiang University Database, or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 14 of 243082 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 14858 chromosomes (freq: 0.0001), Latino in 1 of 33348 chromosomes (freq: 0.00003), European (Non-Finnish) in 7 of 110080 chromosomes (freq: 0.00006), Finnish in 1 of 22236 chromosomes (freq: 0.00005), and South Asian in 3 of 30260 chromosomes (freq: 0.0001); it was not observed in the Other, Ashkenazi Jewish, or East Asian populations. The variant was identified in our lab with a co-occurring pathogenic PMS2 variant (p.Gln719Argfs*6) increasing the likelihood that the p.Thr934Met variant does not have clinical significance. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Thr934 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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