ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.431G>T (p.Ser144Ile) (rs3211299)

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Total submissions: 26
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074988 SCV000108204 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
GeneDx RCV000121570 SCV000170368 benign not specified 2014-01-09 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 RCV000130532 SCV000185401 benign Hereditary cancer-predisposing syndrome 2014-11-10 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 RCV001081952 SCV000252631 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121570 SCV000302879 likely benign not specified criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000121570 SCV000539698 likely benign not specified 2017-01-24 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: This variant has been reported in 18 papers in HGMD - most say that it is benign. Classified in ClinVar as Benign/Likely Benign by 6 submitters (InSiGHT (3 stars), GeneDx, Ambry, Invitae, Prevention Genetics, CSER_CC_NCGL), as VUS by Biesecker lab, and as Pathogenic by Mayo Clinic. MaxMAF = 0.27% - high for disease incidence.
Genetic Services Laboratory, University of Chicago RCV000121570 SCV000595849 likely benign not specified 2016-12-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130532 SCV000685489 likely benign Hereditary cancer-predisposing syndrome 2015-02-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034501 SCV000695914 benign not provided 2016-05-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000121570 SCV000700619 benign not specified 2016-11-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000606030 SCV000745646 benign Hereditary nonpolyposis colorectal cancer type 5 2016-12-09 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000606030 SCV000781780 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034501 SCV000805904 likely benign not provided 2015-04-21 criteria provided, single submitter clinical testing
Mendelics RCV000074988 SCV000837866 likely benign Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121570 SCV000888289 benign not specified 2020-07-10 criteria provided, single submitter clinical testing
Mendelics RCV000606030 SCV001135784 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000606030 SCV001300595 benign Hereditary nonpolyposis colorectal cancer type 5 2018-02-13 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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198193 SCV001369063 uncertain significance Endometrial carcinoma 2019-05-08 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP4,BS1,BS2.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034501 SCV000043350 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000121570 SCV000085766 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148642 SCV000190357 likely benign Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Mayo Clinic Laboratories, Mayo Clinic RCV000034501 SCV000257299 pathogenic not provided no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353551 SCV000592567 likely benign Carcinoma of colon no assertion criteria provided clinical testing MSH6, EXON2, c.431G>T, p.Ser144Ile, Heterozygous, Likely Benign The MSH6 p.Ser144Ile variant was identified in 5 of 4526 proband chromosomes (frequency: 0.001) from individuals or families with HNPCC, suspected HNPCC, or CRC before age 50, and was present in 3 of 1554 control chromosomes (frequency: 0.002) from healthy individuals (Niessen 2006, Nilbert 2009, Okkels 2012, Woods 2005, Bodian 2014). The variant was also identified in dbSNP (ID: rs3211299) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, Ambry Genetics, and 4 other submitters; as likely benign by Prevention Genetics, our laboratory, and 6 other submitters; and as uncertain significance by 2 submitters), LOVD 3.0 (34x), and UMD-LSDB (15x as neutral). In UMD, the variant was identified with multiple co-occurring pathogenic variants: MSH6, c.2906A>G (p.Tyr969Cys); MLH1, c.380G>C (p.Arg127Thr); and MSH2 c.1277_1386del, (p.Lys427GlyfsX4), increasing the likelihood that the p.Ser144Ile variant does not have clinical significance. The variant was identified in control databases in 275 of 277216 chromosomes at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 10 of 24036 chromosomes (freq: 0.0004), Other in 9 of 6466 chromosomes (freq: 0.001), Latino in 29 of 34418 chromosomes (freq: 0.0008), European in 173 of 126702 chromosomes (freq: 0.001), and Finnish in 54 of 25790 chromosomes (freq: 0.002); it was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. Although the p.Ser144 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Ile variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing; this is not very predictive of pathogenicity. Functional and bioinformatics assays show somewhat conflicting results in terms of pathogenicity of this variant: one study showed loss of function for this variant in a yeast assay (Kolodner 1999), while multiple other studies found the interaction of the variant protein with MSH2 and the MMR activity to be comparable to wildtype (Perez-Cabornero 2013, Bameston 2008, Drost 2012, Cyr 2008, Kariola 2002). 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000606030 SCV000734208 likely benign Hereditary nonpolyposis colorectal cancer type 5 no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000034501 SCV001924899 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000121570 SCV001956081 benign not specified no assertion criteria provided clinical testing

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