ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.250A>G (rs63750641)

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Total submissions: 4
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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 RCV001201354 SCV000543580 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-12 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 (ExAC no frequency). This variant has been reported in several individuals with clinical features of Lynch syndrome (PMID: 19419416, 10323887, 26053027, 17453009, 21404117). ClinVar contains an entry for this variant (Variation ID: 90120). This variant has been reported to affect MLH1 protein function (PMID: 21404117, 17510385, 23403630, 15475387, 16083711, 12513688). Based on a multifactorial likelihood algorithm using genetic, clinical, in silico and functional data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV001269582 SCV001449670 likely pathogenic not provided 2017-02-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353981 SCV000592342 likely pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Lys84Glu variant has been reported in the literature in 5 out of 2140 proband chromosomes (frequency of 0.002) from patients with HNPCC; the variant was not reported in any of at least 600 control chromosomes, increasing the likelihood this variant may be a low frequency variant with clinical significance (Ellison 2004, Raevaara 2005, Takahashi 2007, Wanat 2007, Lamberti 1999, Ou 2007, Quaresima 2003, Martinez 2010, Tang 2009, Overbeek 2007). The p.Lys84 residue is conserved across mammals and lower species and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the p.Lys84Glu variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs63750641) but no frequency information was provided so this was not informative for assessing the population frequency. Functional assays using site-directed mutagenesis and in vitro mismatch repair (MMR) assays found the p.Lys84Glu variant to be deficient in MMR function, increasing the likelihood that an alteration to this residue might have clinical significance (Ellison 2004, Raevaara 2005, Takahashi 2007, Wanat 2007, Quaresima 2003). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more pathogenic role for this variant. This variant is classified as Predicted Pathogenic.

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