ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.250A>G (p.Lys84Glu) (rs63750641)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075606 SCV000106603 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Abrogated function & >2 MSI-H tumours
Invitae RCV000075606 SCV000543580 uncertain significance Lynch syndrome 2016-08-08 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 84 of the MLH1 protein (p.Lys84Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (rs63750641, ExAC no frequency). This variant has been reported in several individuals affected with Lynch syndrome or suspected Lynch syndrome (PMID: 19419416, 10323887, 26053027, 17453009, 21404117). ClinVar contains an entry for this variant (Variation ID: 90120). Experimental studies have shown that this missense change alters protein function resulting in deficient mismatch repair activity (PMID: 21404117, 17510385, 23403630, 15475387, 16083711, 12513688). In summary, this variant is absent in the general population, has been identified in several individuals with Lynch syndrome, and disrupts protein function in experimental studies. However, this variant has not yet been shown to segregate with disease in a family. For these reasons, this change has been classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075606 SCV000592342 likely pathogenic Lynch syndrome 2012-07-14 criteria provided, single submitter clinical testing

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