ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1976G>C (p.Arg659Pro) (rs63749900)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075447 SCV000106445 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Abrogated function (MMR activity & aberrant splicing), >2 MSI-H tumours, co-segregation with disease & absent in 1000 genomes
Invitae RCV001064800 SCV001229720 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-04-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 659 of the MLH1 protein (p.Arg659Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Lynch syndrome (PMID: 8776590, 11793442, 16083711, 11601928, 11555625). ClinVar contains an entry for this variant (Variation ID: 89965). This variant has been reported to affect MLH1 protein function (PMID: 9697702, 10037723, 11793442, 12810663, 15864295, 16083711, 17510385). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 10534773, 16995940). 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.

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