ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.83C>T (p.Pro28Leu) (rs63750792)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000075881 SCV000914313 pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
Ambry Genetics RCV000160552 SCV000213763 pathogenic Hereditary cancer-predisposing syndrome 2017-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Integrated Genetics/Laboratory Corporation of America RCV000075881 SCV000696183 pathogenic Lynch syndrome 2016-06-16 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.83C>T (p.Pro28Leu) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121156 control chromosomes. This variant has been reported in multiple affected individuals and functional studies showed that variant causes deficient MMR activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075881 SCV000106897 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000075881 SCV000259722 likely pathogenic Lynch syndrome 2015-08-02 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 28 of the MLH1 protein (p.Pro28Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in the population databases (rs63750792, no frequency), but has been reported in individuals affected with Lynch syndrome, although no segregation data is available (PMID: 9298827, 10323887, 12624141, 16083711, 16451135, 16736289, 17510385, 21404117). ClinVar has an entry for this variant (RCV000160552). Experimental studies have shown that this missense change abrogates the mismatch repair function of the MLH1 protein, which is unable to rescue the functional phenotype presented by MLH1 null cells (PMID: 10082584, 16083711, 17210669, 17510385). For these reasons, this variant has been classified as Likely Pathogenic.

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