Submissions for variant NM_000251.3(MSH2):c.2120G>A (p.Cys707Tyr)

gnomAD frequency: 0.00003  dbSNP: rs373226409

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160602	SCV000211198	uncertain significance	not provided	2022-07-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch syndrome-associated tumors and other cancers, but also in unaffected controls (Rashid et al., 2019; Ryan et al., 2020; Aswath et al., 2021); This variant is associated with the following publications: (PMID: 30122538, 31660093, 32941469, 34426522, 21120944, 18822302, 35415788, 34326811)
Counsyl	RCV000410402	SCV000488196	uncertain significance	Lynch syndrome 1	2016-01-22	criteria provided, single submitter	clinical testing
Invitae	RCV001085231	SCV000559226	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
St. Jude Molecular Pathology, 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 (https://gnomad.broadinstitute.org/variant/2-47703620-G-A). 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 Diagnostics, LLC DBA Color Health	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	2023-08-30	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.
Sema4, Sema4	RCV000491763	SCV002534448	likely benign	Hereditary cancer-predisposing syndrome	2021-11-02	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410402	SCV004018292	benign	Lynch syndrome 1	2023-03-20	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193853	SCV004024762	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000761096	SCV004827829	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
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.