ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.913G>A (p.Ala305Thr) (rs63751454)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656876 SCV000149456 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.913G>A at the cDNA level, p.Ala305Thr (A305T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant was observed in at least three patients suspected of having Lynch syndrome, but a tumor from one of these individuals demonstrated low microsatellite instability and normal MSH2 protein expression (Wijnen 1997, Arnold 2009, Thompson 2013). MSH2 Ala305Thr demonstrated normal mismatch repair activity, binding, and cellular localization; however, the authors that performed these functional analyses were hesitant to call this variant neutral (Lutzen 2008, Drost 2011). The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classifies this variant as being of uncertain significance based on insufficient evidence. MSH2 Ala305Thr was observed at an allele frequency of 0.012% (13/110,622) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ala305Thr is located in the Lever domain (L?tzen 2008, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Ala305Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115547 SCV000213040 likely benign Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);No disease association in small case-control study;Other data supporting benign classification
Invitae RCV001084038 SCV000254431 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115547 SCV000537524 likely benign Hereditary cancer-predisposing syndrome 2019-09-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656876 SCV000601493 uncertain significance not provided 2019-07-04 criteria provided, single submitter clinical testing
Mendelics RCV000076748 SCV000837823 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000986655 SCV001135710 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193245 SCV001361973 likely benign not specified 2020-10-09 criteria provided, single submitter clinical testing Variant summary: MSH2 c.913G>A (p.Ala305Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249030 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (6e-05 vs 0.00057), allowing no conclusion about variant significance. c.913G>A has been reported in the literature in individuals affected with colorectal cancer and/or undergoing panel based genetic testing for Lynch syndrome/Hereditary Nonpolyposis Colorectal Cancer and the NHLBI Exome Sequencing Project (ESP) cohort (example, Winjen_1997, Winjen_1998, Dudley_2018, Buchanan_2016, Amendola_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. Several publications report experimental evidence evaluating an impact on protein function (example, Lutzen_2008, Drost_2011, Bouvet_2019). These results showed no damaging effect of this variant in measures of MMR activity, no defect in nuclear localization, mismatch binding, ATP release, MSH6 binding and EXO1 binding. Seven 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 (likely benign, n=3, VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the reproducible functional evidence and emerging consensus towards a benign outcome as outlined above, the variant was re-classified as likely benign.
CSER _CC_NCGL, University of Washington RCV000148633 SCV000190348 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076748 SCV001549588 uncertain significance Lynch syndrome no assertion criteria provided clinical testing The MSH2 p.Ala305Thr variant was identified in 1 of 368 proband chromosomes (frequency: 0.003) from Dutch individuals or families with HNPCC Lynch Syndrome and was not identified in 200 control chromosomes from healthy individuals (Wijnen 1997, Wijnen 1998). Lutzen et al (2008) used functional assays to show that the variant protein lacks any defect in mismatch binding, ATP-release, MMR activity, subcellular localization or protein-protein interactions. In an in vitro study looking at unclassified variants for possible splicing aberrations, tumours carrying the variant were found to have normal MMR activity, and lymphoblastoid cell line derived cDNA displayed normal wildtype product (Arnold 2009). An in silico model based on multivariate analysis predicted a MAPP-MMR score of 3.55, with anything >4.55 considered deleterious (Chao 2008); while an Australian study using a multifactorial likelihood model predicted the pathogenicity of the variant to be Class 3, (unclassified) (Thompson 2013). The variant was identified in dbSNP (ID: rs63751454) as “With Uncertain significance allele”, Clinvitae database (classification uncertain significance), “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database- (LOVD) (11xX as Class 3), ClinVar database (classification uncertain significance, reviewed by an expert panel, submitters InSIGHT, GeneDx, Ambry Genetics, Invitae and CSER CC NCGL: University of Washington Medical Center), and UMD (1x with ”unclassified variant” classification). This variant was also identified in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles (frequency: 0.0001), and in the Exome Aggregation Consortium database (August 8, 2016) in 6 of 121170 chromosomes (frequency: 0.00005) in the following populations: African in 1 of 10280 chromosomes (frequency: 0.0001) and European (Non-Finnish) in 5 of 66656 chromosomes (frequency: 0.00008), but was not seen in East Asian, European (Finnish), Latino, Other, or South Asian populations. The p.Ala305 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.