ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3217C>T (p.Pro1073Ser) (rs142254875)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074820 SCV000108031 likely benign Lynch syndrome 2018-10-18 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.001-0.049 (0.02)
GeneDx RCV000034498 SCV000149315 likely benign not provided 2020-07-31 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 32547938, 25741868, 28767289, 23621914, 26898890, 27153395, 22703879, 18269114, 22495361, 22290698, 23047549)
Invitae RCV001084149 SCV000166227 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115406 SCV000187203 benign Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study;Other data supporting benign classification;Subpopulation frequency in support of benign classification
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034498 SCV000493608 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000202106 SCV000595855 uncertain significance not specified 2017-06-09 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659894 SCV000781791 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034498 SCV000805883 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing
Mendelics RCV000074820 SCV000837910 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000074820 SCV000887451 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.3217C>T has a 74.5% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Fulgent Genetics,Fulgent Genetics RCV000764428 SCV000895485 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115406 SCV000910560 benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000202106 SCV000919760 benign not specified 2021-01-30 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3217C>T (p.Pro1073Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 251352 control chromosomes, predominantly at a frequency of 0.00023 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 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014). Furthermore, the observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 54 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014). These observations strongly suggest that the variant is benign. c.3217C>T has been reported in the literature in individuals affected with features of HNPCC/Colorectal Cancer (example, Devlin_2008, Okkels_2012, Haraldsdottir_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer (Lynch syndrome). The UMD database reports its presence in individuals with microsatellite stable, IHC positive, sporadic colorectal cancer. A recent study reporting tumor characteristic likelihood ratio (TCLR) in combination with in silico predictors and a multifactorial variant prediction model that included allele frequency, co-occurrence, co-segregation, clinical and family history information, classified this variant as unequivocally benign (Li_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve 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/benign, n=5; VUS, n=7). Based on the evidence outlined above, the variant was classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV000659894 SCV001302732 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-01 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV000659894 SCV001525812 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-03-22 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034498 SCV000043361 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000202106 SCV000257242 uncertain significance not specified no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358558 SCV001554328 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Pro1073Ser variant was identified in 4 of 6780 proband chromosomes (frequency: 0.0006) from individuals or families with Lynch syndrome, ovarian cancer, and colorectal cancer (Okkels 2012, Pal 2012, Haraldsdottir 2017). The variant was also identified in dbSNP (ID: rs142254875) as “With Uncertain significance allele”, in ClinVar (10x as Uncertain Significance by InSiGHT, GeneDx, University of Chicago, Biesecker Lab, Mayo Clinic and Praxis fuer Humangenetik, as Likely Benign by Ambry and as Benign by Invitae), UMD-LSDB (5x and classified as unknown), Mismatch Repair Genes Variant Database (1x), and the Insight Hereditary Tumors Database (1x). The variant was not identified in Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang University Database, or the MMR Gene Unclassified Variants Database. The variant was identified in control databases in 113 of 277092 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 6 of 6466 chromosomes (freq: 0.001), Latino in 1 of 34390 chromosomes (freq: 0.00003), European Non-Finnish in 27 of 126636 chromosomes (freq: 0.0002), Ashkenazi Jewish in 78 of 10150 chromosomes (freq: 0.008), Finnish in 1 of 25786 chromosomes (freq: 0.00004); it was not observed in the African, East Asian, and South Asian populations. The variant was identified in 2 cases both showing normal IHC from a cohort of patients referred to genetics clinic for suspicion of Lynch Syndrome (Okkels 2012). A study developing a bioinformatics tool that integrates prediction results and structural properties classified this variant as having no impact on MSH6 (Terui 2013). The p.Pro1073 residue is not 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, 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.

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