ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.977T>C (p.Val326Ala) (rs63751049)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075951 SCV000106969 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035356 SCV000059004 likely benign not specified 2017-07-27 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000035356 SCV000149399 likely benign not specified 2018-02-23 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.
Invitae RCV000590380 SCV000153900 benign not provided 2019-03-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115490 SCV000187366 likely benign Hereditary cancer-predisposing syndrome 2017-09-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),Does not segregate with disease in family study (genes with incomplete penetrance),No disease association in small case-control study
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000075951 SCV000296892 uncertain significance Lynch syndrome 2015-12-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000035356 SCV000601421 benign not specified 2017-04-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000035356 SCV000604229 uncertain significance not specified 2016-12-29 criteria provided, single submitter clinical testing
Color RCV000115490 SCV000684887 likely benign Hereditary cancer-predisposing syndrome 2015-04-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000035356 SCV000696195 likely benign not specified 2019-01-31 criteria provided, single submitter clinical testing Variant summary: The variant, MLH1 c.977T>C (p.Val326Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 278288 control chromosomes, predominantly at a frequency of 0.0011 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. This variant was found in two affected members from a family and in three affected members from another HNPCC family (Spaepen 2006, Hardt 2011). Detailed genotypic and phenotypic information was not available to assert whether or not the variant co-segregated with disease. In contrast, in one family, this variant did not co-segregate with the disease: while one affected member was positive for the variant, other two affected members did not carry the variant (Pastrello 2011). In addition, tumor tissues from patients with this variant showed no loss of heterozygosity, or loss of expression of MLH1 or MSH2, or microsatellite instability (Dieumegard 2000, Spaepen 2006, Pastrello 2011, Hardt 2011). In vitro MMR and dominant mutator effect studies showed conflicting results (Shimodaira 1998, Trojan 2002, Takahashi 2007) but in vitro assays may not accurately represent biological function. However, the yeast two-hybrid assay showed that hMLH1 V326A can interact with hPMS2 and hEXO1 (Kondo 2003) and the variant was shown to not affect normal splicing (Borras 2012). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and seven of them have classified the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000590380 SCV000805985 likely benign not provided 2017-02-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590380 SCV000888191 benign not provided 2017-04-20 criteria provided, single submitter clinical testing
Mendelics RCV000987161 SCV001136392 likely benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590380 SCV001153840 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing
ITMI RCV000035356 SCV000085539 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144598 SCV000189925 likely benign Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148617 SCV000190332 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000035356 SCV000691852 uncertain significance not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000115490 SCV000886687 likely benign Hereditary cancer-predisposing syndrome 2018-09-27 no assertion criteria provided clinical testing

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