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

gnomAD frequency: 0.01363  dbSNP: rs56371757

Total submissions: 19

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	2024-02-01	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: seen in unaffected individuals, 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.
Eurofins Ntd Llc (ga)	RCV000035320	SCV000203037	benign	not specified	2014-04-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000035320	SCV000302871	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094695	SCV000430971	likely benign	Lynch syndrome 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 Diagnostics, LLC DBA Color Health	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
GeneDx	RCV001668151	SCV001885355	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130484	SCV002535715	benign	Hereditary cancer-predisposing syndrome	2020-01-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000035320	SCV002552309	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001094695	SCV004015995	benign	Lynch syndrome 5	2023-07-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000035320	SCV001808907	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000035320	SCV001924527	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000035320	SCV002035411	benign	not specified		no assertion criteria provided	clinical testing