ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.884A>G (p.Lys295Arg) (rs267608051)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000512927 SCV000149354 likely benign not provided 2021-03-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21437237, 18566915, 23621914, 16010685, 26333163, 26689913, 23047549, 26845104)
Ambry Genetics RCV000115445 SCV000214730 likely benign Hereditary cancer-predisposing syndrome 2019-06-17 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000524217 SCV000254335 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000075042 SCV000266213 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Counsyl RCV000410872 SCV000487810 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-11-18 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212636 SCV000539701 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper, no segs, ExAC: 0.02% (12/66598) European chromosomes
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000512927 SCV000601619 uncertain significance not provided 2019-08-07 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000512927 SCV000608936 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212636 SCV000695929 likely benign not specified 2021-05-10 criteria provided, single submitter clinical testing Variant summary: MSH6 c.884A>G (p.Lys295Arg) results in a conservative amino acid change in 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 9.2e-05 in 251246 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.884A>G has been reported in the literature associated with several types of cancer including but not limited to colorectal adenomas, Lynch syndrome, breast/ovarian cancer, colon cancer (Example: Lu_2015, Shirts_2015, Pal_2012, Nilbert_2009, Colley_2005, VanMarcke_2020). These reports however, do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. One study reports that this variant did not affect MSH6 cellular localization but its proficiency in mismatch repair activity has not been addressed (Gassman_2011). Ten other ClinVar submitters (evaluation after 2014) cite the variant uncertain significance (n=8) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000115445 SCV000910671 likely benign Hereditary cancer-predisposing syndrome 2014-12-09 criteria provided, single submitter clinical testing
Mendelics RCV000410872 SCV001135797 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000410872 SCV001302619 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-08-16 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 RCV000512927 SCV001552237 uncertain significance not provided no assertion criteria provided clinical testing The MSH6 p.Lys295Arg variant was identified in 4 of 8180 proband chromosomes (frequency: 0.0005) from individuals or families with breast or colorectal cancer (Colley 2005, Nilbert 2009, Pal 2012, Shirts 2015). The variant was also identified in dbSNP (ID: rs267608051) as "With Uncertain significance allele ", ClinVar (classified as uncertain significance by InSight, GeneDx, Ambry Genetics, Invitae, Counsyl and five clinical laboratories), UMD-LSDB (2x as unclassified variant), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors (2x) databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, or Zhejiang University, databases. The variant was identified in control databases in 26 of 276994 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 34408 chromosomes (freq: 0.00003), European in 23 of 126552 chromosomes (freq: 0.0002), Finnish in 2 of 25790 chromosomes (freq: 0.00008), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Lys295 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. 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. In addition, in vitro study has shown that variant located in substantial amino-terminal region and does not disrupt MSH6 stability and localization signal. 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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