ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1217G>A (p.Arg406Gln) (rs146567853)

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Total submissions: 10
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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 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000411777 SCV000487968 uncertain significance Lynch syndrome I 2015-12-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765665 SCV000897007 uncertain significance Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc 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 uncertain significance not specified 2018-05-07 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 (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 3.52 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), suggesting that the variant might be a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. To our knowledge, no occurrence of c.1217G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (uncertain significance x2, likely benign x2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212599 SCV001134332 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000411777 SCV001304344 uncertain significance Lynch syndrome I 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.
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.

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