ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.637G>A (p.Val213Met) (rs2308317)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075789 SCV000106799 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
GeneDx RCV000121357 SCV000170290 benign not specified 2014-01-10 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 RCV000128927 SCV000172797 benign Hereditary cancer-predisposing syndrome 2014-10-22 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000121357 SCV000232494 benign not specified 2014-12-29 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000075789 SCV000257653 benign Lynch syndrome 2015-06-08 criteria provided, single submitter clinical testing
Invitae RCV001083249 SCV000262382 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001094789 SCV000443329 likely benign Lynch syndrome II 2018-02-22 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000121357 SCV000539631 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: ExAC: 3.0% African chromosomes
Genetic Services Laboratory, University of Chicago RCV000121357 SCV000595800 likely benign not specified 2016-02-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000034547 SCV000604230 benign not provided 2018-02-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000128927 SCV000684855 benign Hereditary cancer-predisposing syndrome 2015-02-19 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121357 SCV000805978 benign not specified 2017-01-10 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034547 SCV000043320 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000121357 SCV000085537 not provided not specified 2013-09-19 no assertion provided reference population
Mayo Clinic Laboratories, Mayo Clinic RCV000121357 SCV000257109 benign not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000128927 SCV000788025 benign Hereditary cancer-predisposing syndrome 2017-11-14 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355297 SCV001550141 benign Malignant tumor of breast no assertion criteria provided clinical testing The MLH1 p.Val213Met variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs2308317) as With Benign ,Uncertain significance allele , ClinVar (classified as benign by InSight, GenDx, Ambry Genetics, Invitae; classified as likely benign by Illumina), Clinvitae (classified as benign by ClinVar), UMD-LSDB (3X as neutral), Insight Colon Cancer Gene Variant Database (8X class 1), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 733(11 homozygous) of 276886 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 671 of 24030 chromosomes (freq: 0.028). Functional analysis of human MLH1 variants using yeast identify the variant has normal EXO1-binding, normal PMS2-binding and normal MMR function (Kondo 2003, Takahashi 2007). The variant functioned like the WT MLH1 in all of the assays in Raevaara (2005) with normal MMR function, normal nuclear concentration of MLH1 and normal nuclear concentration of the MLH1-PMS2 heterodimer. In addition, the variant has no effect on splicing in the pCAS ExVivo SplicingAssay (Tournier 2008) and concordant with patient RNA. The p.Val213 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Histidine kinase-like ATPase, ATP-binding domain DNA mismatch repair protein family Ribosomal protein S5 domain 2-type fold functional domains increasing the likelihood that it may have clinical significance. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000121357 SCV001807560 benign not specified no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000121357 SCV001920437 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000121357 SCV001952491 benign not specified no assertion criteria provided clinical testing

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