Submissions for variant NM_000179.2(MSH6):c.1186C>G (p.Leu396Val) (rs2020908)

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030259	SCV000107841	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
GeneDx	RCV000121576	SCV000170351	benign	not specified	2013-10-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000157762	SCV000212712	benign	Hereditary cancer-predisposing syndrome	2014-08-20	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.
Invitae	RCV001083342	SCV000262452	benign	Hereditary nonpolyposis colorectal neoplasms	2020-12-04	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000157762	SCV000267054	benign	Hereditary cancer-predisposing syndrome	2015-12-03	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia	RCV000030259	SCV000296878	benign	Lynch syndrome	2015-09-17	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000121576	SCV000302868	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000625241	SCV000430960	likely benign	Hereditary nonpolyposis colorectal cancer type 5	2018-03-06	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	RCV000157762	SCV000537391	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121576	SCV000595841	benign	not specified	2017-06-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000121576	SCV000604277	benign	not specified	2018-07-23	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625241	SCV000744290	benign	Hereditary nonpolyposis colorectal cancer type 5	2015-09-21	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625241	SCV000745648	benign	Hereditary nonpolyposis colorectal cancer type 5	2016-07-11	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc	RCV000625241	SCV000781786	likely benign	Hereditary nonpolyposis colorectal cancer type 5	2016-11-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000625241	SCV001135803	likely benign	Hereditary nonpolyposis colorectal cancer type 5	2019-05-28	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034490	SCV000043352	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030259	SCV000052926	benign	Lynch syndrome	2013-10-16	no assertion criteria provided	clinical testing
ITMI	RCV000121576	SCV000085772	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144628	SCV000189955	benign	Lynch syndrome I	2014-07-24	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000121576	SCV000257209	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001353801	SCV000592581	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Leu396Val variant has been previously reported in about 9/5154 proband chromosomes in individuals with Lynch syndrome, sporadic colorectal cancer and endometrial cancer. It has also been observed in 3/5148 control chromosomes (Kim_2004_15340264, Kolodner_1999_10537275, Martinez_2010_20176959, Niessen_2006_16408224, Nilbert_2009_18566915, Perez-Cabornero_2009_19250818, Schafmayer_2007_17417778, Steinke_2008_18301448, Vahteristo_2005_15805151). It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs2020908) with an average heterozygosity score and standard error of 0.008+/-0.064, and a global minor allele frequency (MAF) of 0.004 (1000 Genomes), increasing the likelihood that this is a benign variant. The variant was also identified as a low frequency variant from HapMap samples of different populations of origin as well as in the EPS project as a low frequency variant increasing the liklihood this variant is benign. This residue is conserved in mammals, and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest this variant may impact protein function. However, this information is not very predictive of pathogenicity. Two functional Saccharomyces cerevisiae-based studies have shown that the MMR activity of the variant is comparable to the wild type protein (Kolodner_1999_10537275, Martinez_2010_20176959), increasing the likelihood that the p.Leu396Val variant is not clinically significant. In summary, based on the above information, this variant is classified as Benign.
True Health Diagnostics	RCV000157762	SCV000788042	benign	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000121576	SCV001798739	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics,Academic Medical Center	RCV000121576	SCV001920906	benign	not specified		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000121576	SCV001958614	benign	not specified		no assertion criteria provided	clinical testing