ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3488A>T (p.Glu1163Val) (rs63750252)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074868 SCV000108080 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research MAF >1% in specific population
GeneDx RCV000121587 SCV000170363 benign not specified 2014-02-18 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 RCV000132123 SCV000187191 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.
Invitae RCV001084016 SCV000260303 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-08 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000121587 SCV000539699 likely benign not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: Lik Ben by expert panel
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121587 SCV000601574 likely benign not specified 2017-03-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132123 SCV000685410 benign Hereditary cancer-predisposing syndrome 2014-12-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587729 SCV000695870 benign not provided 2016-06-01 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3488A>T (p.Glu1163Val) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome. This variant was found in 148/121590 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0137604 (119/8648). This frequency is about 97 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. It was also reported in HNPCC patients, however without strong evidence for pathogenicity such as co-segregation of the variant with the disease in affected family members. Additionally, databases and multiple clinical diagnostic laboratories classify variant as Benign/Likely benign. Considering the high prevalence of the variant in the East Asian population, it was classified as Benign.
PreventionGenetics,PreventionGenetics RCV000121587 SCV000805893 benign not specified 2016-11-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587729 SCV000888276 benign not provided 2018-03-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001137560 SCV001297513 likely benign Hereditary nonpolyposis colorectal cancer type 5 2018-02-09 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ITMI RCV000121587 SCV000085783 not provided not specified 2013-09-19 no assertion provided reference population
Mayo Clinic Laboratories, Mayo Clinic RCV000121587 SCV000257259 uncertain significance not specified no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353894 SCV000592645 benign Carcinoma of colon no assertion criteria provided clinical testing The p.Glu1163Val variant was identified in 4 of 2866 proband chromosomes (frequency: 0.001) from individuals or families with HNPCC and colorectal cancer), and was present in 5 of 642 control chromosomes (frequency: 0.008) from healthy individuals (Ali 2012, Limburg 2011, Nilbert 2009, Shin 2004, Yan 2007). The variant was also identified in dbSNP (ID: rs63750252 “With untested allele”, with a minor allele frequency of 0.0028 (14 of 5000 chromosomes in 1000 Genomes Project). This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 143 of 121316 alleles (frequency: 0.001179) (including 119 of 8648:freq 0.01376 of East Asian chromosomes) and was not found in African and European (Finnish) populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Glu1163Val variant was identified in the Clinvar database and was classified as Benign by GeneDx, Ambry Genetics and Invitae; as Likely Benign by InSIGHT; as a variant of uncertain significance by Mayo Clinic Genetic Testing Laboratory and no classification was provided by ITMI. In UMD Colon Genes database the variant was identified 2X and classified as unknown. The variant co-occurred with a pathogenic MSH2 variant (c.518T>C, p.Leu173Pro). The InSIGHT database identified the variant 7X and classified it as likely not pathogenic and in the Zheijiang database the variant was identified 1X and classified unknown. In COSMIC database the variant was identified in a lymphoid tumour and in a culture. The p.Glu1163 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Valine variant may impact the protein, however this information is not predictive enough to assume pathogenicity. Additionally, in a Chinese population study the c.3488A>T was also found in the controls; the rate was approximately 3.65% (5/137) (Yan 2007). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

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