ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2633T>C (p.Val878Ala) (rs2020912)

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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000030264 SCV000107978 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
Invitae RCV001080582 SCV000153945 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000121581 SCV000170356 benign not specified 2013-10-11 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 RCV000157763 SCV000212713 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
PreventionGenetics,PreventionGenetics RCV000121581 SCV000302872 benign not specified criteria provided, single submitter clinical testing
Color Health, Inc RCV000157763 SCV000537378 benign Hereditary cancer-predisposing syndrome 2015-01-02 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000121581 SCV000595842 benign not specified 2018-09-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282865 SCV000604268 benign none provided 2020-04-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121581 SCV000695820 benign not specified 2016-04-25 criteria provided, single submitter clinical testing Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a medium size and hydrophobic Valine (V) with a small size and hydrophobic Alanine (A). 2/3 in silico tools predict the variant to be neutral (SNPs&GO and mutation taster were not considered due to low reliability index). The variant was observed in the large and broad cohorts of the ExAC project across diverse ethnicities at an allele frequency of 0.52% which exceeds ~ 36 times the maximal expected allele frequency of a disease causing MSH6 allele (0.0142%). Additionally, 4 homozygous occurrences are also reported in ExAC indicating neutrality. The variant was reported in several patients, however without strong evidence for pathogenicity. Independent functional studies concluded the variant to slightly impair MSH6 MMR functions however a large case control study failed to show association between CRC and the variant (Lipkin_NG_2004). Several clinical diagnostic centers and databases classify variant as Benign (without evidence to independently evaluate). Moreover, UMD lists two co-occurrences with the following pathogenic MSH6 variants: c.3268_3274del (p.Glu1090LysfsX23) and c.3514dup (p.Arg1172LysfsX5). Considering all evidence, the variant was classified as Benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000009486 SCV000743210 benign Hereditary nonpolyposis colorectal cancer type 5 2017-07-28 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000009486 SCV000744292 benign Hereditary nonpolyposis colorectal cancer type 5 2015-09-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000009486 SCV000745652 likely benign Hereditary nonpolyposis colorectal cancer type 5 2015-09-22 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000121581 SCV000854909 likely benign not specified 2018-02-23 criteria provided, single submitter clinical testing
Mendelics RCV000009486 SCV001135823 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034495 SCV001152295 likely benign not provided 2018-07-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000009486 SCV001302726 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-04-27 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
OMIM RCV000009486 SCV000029704 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2001-10-01 no assertion criteria provided literature only
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034495 SCV000043358 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000121581 SCV000085777 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148644 SCV000190359 likely benign Colorectal / endometrial cancer 2014-06-01 no assertion criteria provided research
Mayo Clinic Laboratories, Mayo Clinic RCV000121581 SCV000257226 benign not specified no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353988 SCV000592611 likely benign Carcinoma of colon no assertion criteria provided clinical testing The Val878Ala variant has been previously identified in the literature and by our laboratory. More than 39 probands have been cited in the literature including individuals with endometrial cancer, MSI, microsatellite Mutator phenotype (MMP), and individual meeting Amsterdam Criteria for Lynch syndrome (Charames 2000, Barnetson 2008, Jennifer 2008, Wasielewski 2010, Plaschke 2006, Korhonen 2008, Hampel 2006, Ohmiya 2001, Ohmiya 2001, Berends 2002, Peterlongo 2003, Lipkin 2004, Dovrat 2005). However, there was conflicting information as to the relationship of this variant with disease status. This variant was identified in combination with another variant on the other allele in two different individual, one of whom had a nonsense variant (Plaschke 2006, Ohmiya 2001) raising the possibility that this is a benign variant. Furthermore, over 51 control individuals have been identified with this variant in the literature. In one large case control study, 25/2384 cases had this variant and 46/2630 race matched controls (From Northern Israel and Haifa) were carriers of this variant (Lipkin 2004). The variant has also been observed in other populations at lower frequency (dbSNP:rs2020912). This variant is conserved in mammals and other vertebrates but not in fruitfly. In-silico analysis (Sift, AlignGVGD, MAPP) provide conflicting data, and this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with absolute certainty but we would lean towards a more likely benign role for this variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000009486 SCV000734215 benign Hereditary nonpolyposis colorectal cancer type 5 no assertion criteria provided clinical testing
True Health Diagnostics RCV000157763 SCV000788047 benign Hereditary cancer-predisposing syndrome 2018-09-11 no assertion criteria provided clinical testing
Center of Medical Genetics and Primary Health Care RCV001269491 SCV001449145 benign Malignant tumor of breast no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000121581 SCV001905703 benign not specified no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000121581 SCV001920979 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000121581 SCV001957734 benign not specified no assertion criteria provided clinical testing

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