ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1217G>A (p.Arg406Gln)

gnomAD frequency: 0.00008  dbSNP: rs146567853
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132166 SCV000187243 likely benign Hereditary cancer-predisposing syndrome 2019-03-01 criteria provided, single submitter clinical testing Other data supporting benign classification;Subpopulation frequency in support of benign classification
GeneDx RCV000212599 SCV000211174 uncertain significance not provided 2018-10-12 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1217G>A at the cDNA level, p.Arg406Gln (R406Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been observed in an individual with a history of a single sebaceous adenoma showing loss of MSH2 (Thompson 2014), and in at least one individual with advanced cancer of unspecified type (Mandelker 2017). MSH2 Arg406Gln was observed at an allele frequency of 0.2% (20/10,146) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located within the Lever domain and in the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain due to insufficient evidence (Thompson 2014). Based on currently available evidence, it is unclear whether MSH2 Arg406Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001083003 SCV000218887 likely benign Hereditary nonpolyposis colorectal neoplasms 2021-12-17 criteria provided, single submitter clinical testing
Counsyl RCV000411777 SCV000487968 uncertain significance Lynch syndrome 1 2015-12-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765665 SCV000897007 uncertain significance Lynch syndrome 1; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000132166 SCV000902657 likely benign Hereditary cancer-predisposing syndrome 2015-12-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781558 SCV000919698 likely benign not specified 2022-02-17 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1217G>A (p.Arg406Gln) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251406 control chromosomes (gnomAD), predominantly at a frequency of 0.002 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. To our knowledge, c.1217G>A has not been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating an impact on protein function has been reported. A recent case-control study showed that this variant was not associated with breast cancer (Dorling_2021). Ten ClinVar submitters have assessed the variant since 2014: six have classified the variant as of uncertain significance and four as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212599 SCV001134332 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000411777 SCV001304344 uncertain significance Lynch syndrome 1 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798264 SCV002042087 uncertain significance Breast and/or ovarian cancer 2021-01-28 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000781558 SCV002070224 uncertain significance not specified 2020-05-11 criteria provided, single submitter clinical testing DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1217G>A, in exon 7 that results in an amino acid change, p.Arg406Gln. This sequence change does not appear to have been previously described in patients with MSH2-related disorders and has been described in the EXAC database with a low population frequency of 0.19% in the Ashkenazi Jewish subpopulation (dbSNP rs146567853). The p.Arg406Gln change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg406Gln substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg406Gln change remains unknown at this time.
Sema4,Sema4 RCV000132166 SCV002528822 likely benign Hereditary cancer-predisposing syndrome 2021-04-28 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356152 SCV001551234 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.Arg406Gln variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from individuals or families with advanced cancer, type not specified (Mandelker 2017). The variant was also identified in dbSNP (ID: rs146567853) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics and Invitae; and as uncertain significance by GeneDx, Counsyl, Fulgent, and InSiGHT), and COSMIC databases (confirmed somatic in adenocarcinoma of the large intestine). The variant was not identified in GeneInsight-COGR, MutDB, Mismatch Repair Genes Variant Database, or UMD-LSDB databases. The variant was identified in control databases in 24 of 277084 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 20 of 10146 chromosomes (freq: 0.002, increasing the likelihood this could be a low frequency benign variant), Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 2 of 34418 chromosomes (freq: 0.00006), and European Non-Finnish in 1 of 126604 chromosomes (freq: 0.000008), while the variant was not observed in the African, East Asian, European Finnish, or South Asian populations. 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. The p.Arg406 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. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.