ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1984A>C (p.Thr662Pro) (rs587778964)

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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) RCV000075450 SCV000106447 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Abrogated function (2 independent assays with reduced expression) & 6 MSI-H tumours
Invitae RCV000524263 SCV000260401 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 662 of the MLH1 protein (p.Thr662Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families affected with Lynch syndrome (PMID: 11726306, 11754112, 16341550, 19621678, 21404117). ClinVar contains an entry for this variant (Variation ID: 89968). This variant has been reported to affect MLH1 protein function (PMID: 17510385, 20533529, 23403630). 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.
Integrated Genetics/Laboratory Corporation of America RCV000780422 SCV000917665 uncertain significance not specified 2018-12-11 criteria provided, single submitter clinical testing Variant summary: The variant, MLH1 c.1984A>C (p.Thr662Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In vitro/vivo studies have shown that this variant results in a partial deletion of exon 17, reduces interaction with PMS2, and significantly reduces protein expression (Pagenstecher_2006, Kosinski_2010, Hinrichsen_2013). The variant, when expressed from cDNA, has been shown not to have a significant reduction in MMR activity by multiple studies, however, the MMR proficiency of the partial deletion of exon 17 caused by the variant was not addressed (Takahashi_2007, Hinrichsen_2013). The variant was absent in 276836 control chromosomes (gnomAD and publications) and has been reported in the literature in individuals affected with Lynch Syndrome (Hardt_2011, Pagenstecher_2006, Kruger_2001, Takahashi_2007). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified this variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS possibly pathogenic.
Ambry Genetics RCV001013906 SCV001174548 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-07 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other data supporting pathogenic classification;Rarity in general population databases (dbsnp, esp, 1000 genomes)

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