ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1255C>A (p.Gln419Lys)

gnomAD frequency: 0.00019  dbSNP: rs63750006
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076079 SCV000107094 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx RCV000759096 SCV000211245 likely benign not provided 2019-05-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 8690195, 22995991, 19419416, 23526924, 23741719, 11048710, 10469597, 23760103, 22290698, 17594722, 22283331, 25110875, 24728327, 12792735, 25106712, 17011982, 21155023, 15996210, 26951660, 24078570, 27487738, 26332594, 28580595, 29731845, 31386297)
Ambry Genetics RCV000160643 SCV000213572 likely benign Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV001079969 SCV000260558 benign Hereditary nonpolyposis colorectal neoplasms 2021-12-15 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000160643 SCV000537420 likely benign Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121568 SCV000601426 likely benign not specified 2016-10-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759096 SCV000888201 benign not provided 2017-12-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121568 SCV000917686 benign not specified 2021-03-19 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1255C>A (p.Gln419Lys) results in a conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 252292 control chromosomes, predominantly at a frequency of 0.0075 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13 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.1255C>A has been reported in the literature in individuals affected with Lynch Syndrome (e.g. Tang_2009, Yap_2009) or Breast Cancer (e.g. Shin_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.6952C>T, p.R2318*), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000986666 SCV001135724 benign Lynch syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030708 SCV001193630 benign Hereditary breast ovarian cancer syndrome 2022-03-30 criteria provided, single submitter research
Illumina Laboratory Services,Illumina RCV000986666 SCV001304345 likely benign Lynch syndrome 1 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory,University of Chicago RCV000121568 SCV002070660 likely benign not specified 2019-05-03 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000160643 SCV002528825 benign Hereditary cancer-predisposing syndrome 2021-03-05 criteria provided, single submitter curation
ITMI RCV000121568 SCV000085764 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355791 SCV001550774 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH2 p.Gln419Lys variant was identified in 8 of 10182 proband chromosomes (frequency: 0.001) from individuals or families with gastric cancer, colorectal and stomach cancer and was present in 2 of 2186 control chromosomes (frequency: 0.001) from healthy individuals (Fan 2005, Kang 2015, Lee 2005, Tang 2009, Bodian 2014). The variant was also identified in dbSNP (ID: rs63750006) as With Likely benign, Pathogenic allele, ClinVar (classified as likely benign by GeneDx, Ambry Genetics, Color Genomics, InSight; classified as benign by Invitae), Clinvitae, MutDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was not identified in the COGR, Cosmic, or UMD-LSDB. The variant was identified in control databases in 147 of 277056 chromosomes (1 homozygous) at a frequency of 0.001 (Genome Aggregation Database Feb 27, 2017). It was identified in the following populations: East Asian in 147 of 18866 chromosomes (freq: 0.01); but not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Gln419 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. One study suggested that the glutamine to lysine substitution may influence the conformation of this domain and the function of the gene. And predispose humans to gastric cancer (Fan 2005). In addition, Drotschmann (1999) studied yeast carrying Gln430Lys (the putative equivalents of Gln419Lys in hMSH2), which yielded significant mutator effects, indicating a functional defect and may predispose humans to disease. 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. This variant is classified as likely benign.

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