ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.544A>G (p.Arg182Gly) (rs63750211)

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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) RCV000075747 SCV000106755 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration which introduces frameshift (no full-length expressed from allele)
Invitae RCV000684818 SCV000255269 pathogenic Hereditary nonpolyposis colon cancer 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 182 of the MLH1 protein (p.Arg182Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in multiple individuals with Lynch syndrome and associated cancers, with evidence of segregation with disease (PMID: 21404117, 16395668, 10480359, 22773173, 19459153). ClinVar contains an entry for this variant (Variation ID: 90258). Based on a multifactorial likelihood algorithm using genetic, in silico, and tumor data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Experimental studies in lymphoblastoid cell lines derived from patients carrying this variant have shown that it disrupts splicing, leading to a deletion of exon 6 (PMID: 16395668). Loss of exon 6 causes a frameshift at codon 152, creating a premature translational stop signal (p.Glu153Phefs*8) and is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075747 SCV000592362 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Ambry Genetics RCV000570187 SCV000669544 pathogenic Hereditary cancer-predisposing syndrome 2016-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Good segregation with disease (lod 1.5-3 = 5-9 meioses),Other strong data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation

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