ClinVar Miner

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

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Total submissions: 9
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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 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 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
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761096 SCV000891011 likely benign Lynch syndrome 2020-12-02 criteria provided, single submitter clinical testing The MSH2 c.2120G>A (p.Cys707Tyr) missense change has a maximum subpopulation frequency of 0.33% in gnomAD v2.1.1 ( This population frequency is higher than expected for a pathogenic variant in MSH2 causing Lynch syndrome (BS1). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. A case control study of MSH2 variants identified the p.C707Y variant in 1.4% of cases with colorectal cancer and/or suspected Lynch syndrome and in 2% of healthy controls (BS2_Supporting, PMID: 31660093). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BS2_Supporting, PP3.
Color Health, Inc 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354130 SCV001548671 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.Cys707Tyr variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs373226409) as “with uncertain significance allele” and ClinVar (classified as likely benign by Invitae, Ambry Genetics and Color; and as uncertain significance by GeneDx, Counsyl and one other submitter). The variant was identified in control databases in 109 of 277,212 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 101 of 30,782 chromosomes (freq: 0.003, increasing the likelihood this could be a low frequency benign variant) and European in 8 of 126,714 chromosomes (freq: 0.00006); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian or Finnish populations. The variant was identified by our laboratory as co-occurring with a pathogenic variant in MLH1 (p.Ser44Phe). The p.Cys707 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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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