ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2272C>T (p.Leu758=) (rs56371757)

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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) RCV000074728 SCV000107937 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research MAF >1%
Invitae RCV000524138 SCV000153935 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130484 SCV000185353 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 RCV000035320 SCV000203037 benign not specified 2014-04-11 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000035320 SCV000302871 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001094695 SCV000430971 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 RCV000130484 SCV000685274 benign Hereditary cancer-predisposing syndrome 2015-04-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000035320 SCV001158620 benign not specified 2019-02-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035320 SCV000058968 likely benign not specified 2008-07-10 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000035320 SCV000257222 benign not specified no assertion criteria provided research
True Health Diagnostics RCV000130484 SCV000788046 likely benign Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357393 SCV001552859 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Leu758= variant was identified in 6 of 524 proband chromosomes (frequency: 0.01) from individuals or families with CRC and was not identified in 710 control chromosomes from healthy individuals (de Abajo 2005, Dovrat 2005, Pinto 2006). In one patient from a short family, the c.2272C>T variant was seen along with another silent variant c.1164C>T, occurring on the same chromosome; the proband was diagnosed with colorectal cancer at 29, her sibling was healthy, and her father was diagnosed with larynx cancer at 50 years of age (de Abajo 2005). The variant was identified in dbSNP (ID: rs56371757) as “with other allele”. The variant was also identified in ClinVar as benign by InSiGHT, Invitae, Ambry Genetics, EGL Genetic Diagnostic, Eurofins Clinical Diagnostics, Prevention Genetics and Mayo Clinic Genetic Testing Laboratories: and as likely benign by Illumina Clinical Services and Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine. Furthermore, the variant is listed in the Clinvitae database as benign by Invitae and Emyclass; in Insight Colon Cancer Gene Variant Database 4X as Class 1 and in Insight Hereditary Tumors Database 4X as Class 1. In addition, the variant is listed in the 1000 Genomes Project in 74 of 5000 chromosomes (frequency: 0.01) and in the NHLBI GO Exome Sequencing Project in 4 of 8600 European American and 160 of 4406 African American alleles. The variant was not identified in Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, or Mismatch Repair Genes Variant databases. The variant was identified in control databases in 1212 of 276758 chromosomes (26 homozygous) at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1040 of 24014 chromosomes (freq: 0.04), “other” in 18 of 6456 chromosomes (freq: 0.003), Latino in 119 of 34414 chromosomes (freq: 0.003), European Non-Finnish in 35 of 126308 chromosomes (freq: 0.0003); it was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Leu758= 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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