ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3245C>T (p.Pro1082Leu) (rs191109849)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656898 SCV000149318 likely benign not provided 2021-05-07 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23621914, 24072394, 24728327, 22290698, 25503501, 27498913, 29368341)
Ambry Genetics RCV000115409 SCV000185751 likely benign Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);No disease association in small case-control study;Structural Evidence
Invitae RCV001085899 SCV000254309 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115409 SCV000537600 likely benign Hereditary cancer-predisposing syndrome 2020-03-17 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656898 SCV000805884 uncertain significance not provided 2017-07-11 criteria provided, single submitter clinical testing
Mendelics RCV000074824 SCV000837911 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121583 SCV000919724 benign not specified 2020-11-06 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3245C>T (p.Pro1082Leu) results in a non-conservative amino acid change located in the 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 0.00034 in 252712 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD database, v2.1 exomes dataset. In addition, the variant was reported in Latino control individuals in the gnomAD database, v3.1 genomes dataset with an even higher frequency (i.e. 0.0038), including 2 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 10 to 30-fold higher than 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. c.3245C>T has been reported in the literature in individuals affected with (suspected) Lynch syndrome, and breast-, ovarian- or prostate cancer (Zahary_2014, Maxwell_2015, Kalady_2015, Isaaccon Velho_2018, Xiao_2020, Choi_2020). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.45delT (p.Asn16MetfsX7) and BARD1 c.55G>T ( p.Glu19X), both pathogenic variants have been reported in one specimen tested at our laboratory; and MLH1 c.345_349delTACAA (p.Thr116Glufs*4) in Xiao_2020; and BRCA1 c.3020delC (p.Ser1007*) in Choi_2020), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other 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 (i.e. 4 calling it likely benign, and 4 classifying it as a VUS). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656898 SCV001134425 likely benign not provided 2020-05-29 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656898 SCV001152300 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000656898 SCV001713987 uncertain significance not provided 2019-11-03 criteria provided, single submitter clinical testing
ITMI RCV000121583 SCV000085779 not provided not specified 2013-09-19 no assertion provided reference population
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093655 SCV001250835 uncertain significance Lynch syndrome I no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358430 SCV001554159 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Pro1082Leu variant was identified in 1 of 526 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Kalady 2015). The variant was also identified in dbSNP (ID: rs191109849) as with uncertain significance allele; in the ClinVar and Clinvitae databases as uncertain significance by InSiGHT, Gene Dx, Ambry Genetics, Color Genomics and as likely benign by Invitae. Furthermore, the variant was identified 1X in the Cosmic database and categorized as pathogenic with a FATHMM prediction score of 0.96, with the liver being the primary tissue of origin. The variant was also listed in the Insight Colon Cancer Gene Variant and Insight Hereditary Tumors Databases 2X as class 3. The variant was not identified in the GeneInsight-COGR, MutDB, UMD-LSDB, Zhejiang University, and the Mismatch Repair Genes Variant databases. The variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004) and in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles. The variant was identified in control databases in 85 of 277152 chromosomes at a frequency of 0.0003 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: African in 2 of 24032 chromosomes (freq: 0.00008), Other in 5 of 6462 chromosomes (freq: 0.000774), Latino in 52 of 34400 chromosomes (freq: 0.001), European Non-Finnish in 16 of 126676 chromosomes (freq: 0.0001), East Asian in 6 of 18860 chromosomes (freq: 0.0003), European Finnish in 1 of 25790 chromosomes (freq: 0.00004), and South Asian in 3 of 30782 chromosomes (freq: 0.0001), while the variant was not observed in the Ashkenazi Jewish, populations. In one study, 616 MMR missense variants for Lynch syndrome patients were downloaded (January 27, 2011) from the International Society for Gastrointestinal Hereditary Tumours (In-SiGHT) database. The purpose was to develop a new consensus predictor to identify variants that are highly likely to be pathogenic, neutral, or of unknown pathogenicity status, this was subsequently applied to the 616 MMR cases and the p.Pro1082Leu variant was assigned a neutral category (Ali 2012). The p.Pro1082 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, 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 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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