ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1217G>A (p.Ser406Asn) (rs41294980)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075152 SCV000106144 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
Invitae RCV000034539 SCV000166242 benign not provided 2019-03-05 criteria provided, single submitter clinical testing
GeneDx RCV000121359 SCV000170295 benign not specified 2013-12-19 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 RCV000130336 SCV000185186 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000121359 SCV000225492 likely benign not specified 2014-11-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000121359 SCV000539640 uncertain significance not specified 2017-01-10 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 is present at 0.13% in gnomAD (171/126520 European chrs). It is classified in ClinVar with 3 stars as Likely benign or benign by InSiGHT (Expert panel), Invitae, GeneDx, Ambry, Emory, Mayo, and as VUS by Biesecker lab. It is not a poorly conserved AA but no species has Asn at this position. It is present in 15 papers in HGMD (classified as DM?), most comments say it is not pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000121359 SCV000592400 benign not specified 2017-07-28 criteria provided, single submitter clinical testing
Color RCV000130336 SCV000684730 likely benign Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000034539 SCV000696101 benign not provided 2016-03-07 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1217G>A variant affects a non-conserved nucleotide, resulting in an amino acid change from Ser to Asn. 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index). In vitro MMR assay has shown that this variant has ~75% of wild-type activity and interacts with EXO1 and PMS2 similar to wild-type in a yeast two-hybrid assay. This variant is found in 115/123542 control chromosomes at a frequency of 0.0009309, which exceeds the maximal expected frequency of a pathogenic allele (0.0007105). Additionally, multiple reputable diagnostic labs and databases have classified this variant as benign/neutral. Taken together, this variant was classified as benign.
PreventionGenetics,PreventionGenetics RCV000034539 SCV000805944 likely benign not provided 2017-04-06 criteria provided, single submitter clinical testing
Mendelics RCV000987170 SCV001136403 likely benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034539 SCV001153841 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034539 SCV000043324 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000121359 SCV000085540 not provided not specified 2013-09-19 no assertion provided reference population
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000121359 SCV000257048 benign not specified no assertion criteria provided research
True Health Diagnostics RCV000130336 SCV000886683 likely benign Hereditary cancer-predisposing syndrome 2018-07-13 no assertion criteria provided clinical testing

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