ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1164C>T (p.His388=) (rs55708305)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074639 SCV000107839 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research MAF >1% & Multifactorial likelihood analysis posterior probability <0.001
Invitae RCV000524102 SCV000153934 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130493 SCV000185362 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000035317 SCV000203035 benign not specified 2014-04-11 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000035317 SCV000302866 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001094632 SCV000430958 likely benign Hereditary nonpolyposis colorectal cancer type 5 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color Health, Inc RCV000130493 SCV000685173 benign Hereditary cancer-predisposing syndrome 2015-04-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000035317 SCV001158618 benign not specified 2019-02-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035317 SCV000058965 likely benign not specified 2008-07-10 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000035317 SCV000257206 benign not specified no assertion criteria provided research
True Health Diagnostics RCV000130493 SCV000788041 likely benign Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356459 SCV001551636 benign Endometrial carcinoma no assertion criteria provided clinical testing The MSH6 p.His388= variant was identified in 4 of 908 proband chromosomes (frequency: 0.004) from cases with high risk breast and colon cancer and was not identified in 332 chromosomes from healthy individuals (Kolodner 1999, Perez-Cabornero 2009, Sanchez 2005, Wasielewski 2009). The variant was identified in the following databases: dbSNP (ID: rs55708305) “With other allele”, ClinVar (classified benign, reviewed by an expert panel 2013, submitters: benign by InSIGHT, Invitae, Ambry Genetics, EGL Genetic Diagnostics, Prevention Genetics and Mayo Clinic, and likely benign by Illumina and the Laboratory for Molecular Medicine), Clinvitae (4x), UMD-LSDB (8x neutral), Insight Colon Cancer Gene Variant Database (4x), Mismatch Repair Genes Variant Database (3x), Insight Hereditary Tumors Database (4x) and was not identified in Cosmic, MutDB, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 1240 (29 homozygous) of 276736 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 1060 of 24012 chromosomes (freq: 0.04), Other in 18 of 6454 chromosomes (freq: 0.003), Latino in 125 of 34402 chromosomes (freq: 0.004), European Non-Finnish in 37 of 126300 chromosomes (freq: 0.0003); it was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.His388= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 this variant meets our laboratory's criteria to be classified as benign.

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