ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1121A>G (p.Gln374Arg) (rs749660228)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213803 SCV000274912 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing The p.Q374R variant (also known as c.1121A>G), located in coding exon 7 of the MSH2 gene, results from an A to G substitution at nucleotide position 1121. The glutamine at codon 374 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000213803 SCV000537574 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-16 criteria provided, single submitter clinical testing
GeneDx RCV000483512 SCV000570798 uncertain significance not provided 2017-01-04 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1121A>G at the cDNA level, p.Gln374Arg (Q374R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gln374Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Gln374Arg occurs at a position that is conserved across species and is located in the lever domain (Lützen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Gln374Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001080950 SCV001012810 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 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 I 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)
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093680 SCV001250861 uncertain significance Lynch syndrome I 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.

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