ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2398G>C (p.Val800Leu) (rs61748083)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000680176 SCV000107953 likely benign Lynch syndrome I 2018-06-13 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability < 0.05 (0.028)
GeneDx RCV000656572 SCV000149298 likely benign not provided 2018-12-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115389 SCV000185791 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000524141 SCV000218910 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 800 of the MSH6 protein (p.Val800Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs61748083, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with colorectal, ovarian and kidney cancer (PMID: 10537275, 23047549, 26845104, 26689913), suspected Lynch syndrome (PMID: 15340264), and also unaffected control individuals (PMID: 10537275, 25637381). ClinVar contains an entry for this variant (Variation ID: 89279). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and algorithms developed specifically for the MSH6 gene (PMID: 22290698, 23621914), all suggest that this missense change is likely to be tolerated. 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000074744 SCV000266206 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Counsyl RCV000409574 SCV000487846 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-11-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212665 SCV000539702 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: 3 papers, all describe as VUS/non-pathogenic; ExAC: 2/11540 Latino chromosomes
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212665 SCV000592608 likely benign not specified 2013-06-18 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656572 SCV000805864 uncertain significance not provided 2017-12-08 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115389 SCV000822062 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000115389 SCV000902678 likely benign Hereditary cancer-predisposing syndrome 2015-12-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212665 SCV000917771 uncertain significance not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2398G>C (p.Val800Leu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.41 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2398G>C has been reported in the literature in individuals affected with ovarian cancer (Pal_2012), renal cell carcinoma (Lu_2015), and colorectal cancer (Kim_2004, Kolodner_1999, Shirts_2015), and in one report with positive segregation data, although the number of affected individuals in the family was not reported (Liccardo_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS.
Mendelics RCV000409574 SCV001135818 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212665 SCV001158690 uncertain significance not specified 2019-05-07 criteria provided, single submitter clinical testing The MSH6 c.2398G>C; p.Val800Leu variant (rs61748083) is reported in the literature in individuals with colorectal cancer or ovarian cancer (Kim 2004, Kolodner 1999, Pal 2012, Shirts 2016), but is also reported in a healthy control (Kolodner 1999). This variant is reported in ClinVar (Variation ID: 89279). It is found in the general population with an overall allele frequency of 0.009% (26/282172 alleles) in the Genome Aggregation Database. The valine at codon 800 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Kim JC et al. Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients. Fam Cancer. 2004;3(2):129-37. Kolodner RD et al. Germ-line msh6 mutations in colorectal cancer families. Cancer Res. 1999 Oct 15;59(20):5068-74. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. Shirts BH et al. Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med. 2016 Oct;18(10):974-81.
CSER _CC_NCGL, University of Washington RCV000148650 SCV000190365 uncertain significance Colorectal cancer 2014-06-01 no assertion criteria provided research
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000656572 SCV000778620 uncertain significance not provided 2018-02-20 no assertion criteria provided clinical testing

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