ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3438+11_3438+14del

gnomAD frequency: 0.00023  dbSNP: rs377746844
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160727 SCV000211361 benign Hereditary cancer-predisposing syndrome 2014-05-28 criteria provided, single submitter clinical testing The variant is found in BR-OV-HEREDIC panel(s).
Counsyl RCV000409153 SCV000489397 likely benign Colorectal cancer, hereditary nonpolyposis, type 5 2016-09-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587375 SCV000695864 benign not provided 2017-04-12 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3438+11_3438+14delCTTA variant involves the alteration of 4 intronic nucleotides. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 27/120966 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.002081 (18/8650). This frequency is about 15 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. Multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Additionally, the variant was detected in an internal specimen which also carries likely pathogenic MLH1 c.347delC. Taken together, this variant is classified as benign.
PreventionGenetics,PreventionGenetics RCV000587375 SCV000805889 likely benign not provided 2017-05-04 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000160727 SCV000902634 likely benign Hereditary cancer-predisposing syndrome 2015-04-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587375 SCV001134430 benign not provided 2018-11-15 criteria provided, single submitter clinical testing
Invitae RCV001517158 SCV001725599 benign Hereditary nonpolyposis colorectal neoplasms 2021-12-17 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000587375 SCV002050168 benign not provided 2021-06-11 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001818237 SCV002071216 likely benign not specified 2021-08-02 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000160727 SCV002528025 benign Hereditary cancer-predisposing syndrome 2021-06-10 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074851 SCV000592641 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MSH6 c.3438+11_3438+14del variant was identified in 1 of 68 proband chromosomes (frequency: 0.015) from individuals or families with Lynch syndrome (Chan 1999). The variant was also identified in the following databases: dbSNP (ID: rs377746844) as “With Uncertain significance allele”, ClinVar (as uncertain significance, reviewed by expert panel), Clinvitae (as benign, likely benign, and uncertain significance), COGR, Insight Colon Cancer Gene Variant Database (as Class 3: uncertain), and Insight Hereditary Tumors Database (as Class 3: uncertain). The variant was not identified in Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was identified by our laboratory in 2 individuals with Lynch syndrome. The variant was identified in control databases in 63 of 277008 chromosomes (1 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: East Asian in 39 of 18864 chromosomes (freq: 0.002), “Other” in 5 of 6460 chromosomes (freq: 0.0008), African in 9 of 24016 chromosomes (freq: 0.0004), European Non-Finnish in 9 of 126542 chromosomes (freq: 0.00007), South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, European (Finnish), and Latino populations. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the loss of a cryptic splice acceptor site. 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000587375 SCV001977761 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000587375 SCV001979149 likely benign not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000587375 SCV002035958 likely benign not provided no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001818237 SCV002552339 likely benign not specified 2022-05-17 no assertion criteria provided clinical testing

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