Submissions for variant NM_000251.3(MSH2):c.1121A>G (p.Gln374Arg)

gnomAD frequency: 0.00004  dbSNP: rs749660228

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213803	SCV000274912	benign	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Color Diagnostics, LLC DBA Color Health	RCV000213803	SCV000537574	likely benign	Hereditary cancer-predisposing syndrome	2021-03-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000483512	SCV000570798	uncertain significance	not provided	2020-03-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28009993)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080950	SCV001012810	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175089	SCV001338657	likely benign	not specified	2020-04-23	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1121A>G (p.Gln374Arg) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain of 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 6.8e-05 in 251398 control chromosomes, predominantly at a frequency of 0.00092 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.62 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 East Asian origin. c.1121A>G has been reported in the literature in a cohort of colorectal cancer patients without strong evidence for causality (Toh_2018). This report does 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 likley benign. Based on the evidence outlined above, the variant was classified as likely benign.
Division of Medical Genetics, University of Washington	RCV001093680	SCV001434267	uncertain significance	Lynch syndrome 1	2019-11-25	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.00007072 in the Broad Institute gnomAD Browser; however, this variant has only been observed in individuals with East Asian ancestry at an allele frequency of 0.001002 (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function are mixed with regards to the effect of this variant and there are no functional studies to verify or refute these predictions. Therefore, we interpret this variant as a variant of uncertain significance. (No codes)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491975	SCV004239269	benign	Breast and/or ovarian cancer	2023-05-25	criteria provided, single submitter	clinical testing
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093680	SCV001250861	uncertain significance	Lynch syndrome 1		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355857	SCV001550862	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Gln374Arg variant was not identified in the literature nor was it identified in the following databases: COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs749660228) “With Uncertain significance allele”, ClinVar (classified uncertain significance by Ambry Genetics, Color Genomics Inc. and GeneDx), Clinvitae (2x), and in control databases in 21 of 277204 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 21 of 18868 chromosomes (freq: 0.001); it was not observed in the African, “Other”, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Gln374 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Arg impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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. 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.