ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2120G>A (p.Cys707Tyr) (rs373226409)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160602 SCV000211198 uncertain significance not provided 2018-08-29 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2120G>A at the cDNA level, p.Cys707Tyr (C707Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Cys707Tyr was observed at an allele frequency of 0.33% (101/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the ATPcase domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Cys707Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000410402 SCV000488196 uncertain significance Lynch syndrome I 2016-01-22 criteria provided, single submitter clinical testing
Invitae RCV001085231 SCV000559226 likely benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491763 SCV000580507 likely benign Hereditary cancer-predisposing syndrome 2019-02-01 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification
Color RCV000491763 SCV000902862 likely benign Hereditary cancer-predisposing syndrome 2017-06-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160602 SCV001134351 benign not provided 2019-07-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193853 SCV001363001 benign not specified 2019-02-07 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2120G>A (p.Cys707Tyr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 277212 control chromosomes, predominantly at a frequency of 0.0033 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.2120G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (2x) and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761096 SCV000891011 uncertain significance B lymphoblastic leukemia lymphoma with hyperdiploidy 2016-09-14 no assertion criteria provided clinical testing

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