ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2517T>A (p.His839Gln) (rs267608016)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524391 SCV000254411 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-08-27 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 839 of the MSH2 protein (p.His839Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs267608016, ExAC 0.001%). This variant has been reported in individuals affected with Lynch Syndrome (PMID: 18561205) and colorectal cancer (PMID: 18383312). ClinVar contains an entry for this variant (Variation ID: 90991). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) and an algorithm developed specifically for the MSH2 gene (PMID: 18383312) all suggest that this missense change is likely to be tolerated, although these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000216575 SCV000275133 likely benign Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000479296 SCV000567949 uncertain significance not provided 2021-04-01 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal or family history suggestive of Lynch syndrome (Chao 2008, Tournier 2008); This variant is associated with the following publications: (PMID: 18561205, 18383312, 26333163, 30798936)
Color Health, Inc RCV000216575 SCV000904009 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357139 SCV001552507 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.His839Gln variant was identified in 1 of 28 proband chromosomes (frequency: 0.04) from individuals or families with Lynch syndrome and was absent from 200 control chromosomes; however, the variant was also identified in 5 of 6 of the proband’s healthy relatives (Yuan 2004). The variant was identified in dbSNP (ID: rs267608016 as "With Uncertain significance allele"), ClinVar (1x as likely benign by Ambry Genetics and 3x as uncertain significance by InSight, Invitae, and GeneDx), UMD-LSDB (1x as unclassified variant), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database (9x as class 3). The variant was not identified in COGR, Cosmic, MutDB, or the Zhejiang University Database. The variant was identified in control databases in 5 of 277214 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 5 of 126712 chromosomes (freq: 0.00004), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His839 residue is conserved in mammals but not in more distantly related organisms and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence, however 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this information is not predictive enough to assume pathogenicity. Further, functional analysis using the pCAS ex vivo splicing assay demonstrated this variant had no effect on splicing (Tournier 2008). 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.