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MLH1 c.1852_1853delinsGC (aka c.1852_1853AA>GC, Lys618Ala)

MLH1 c.1852_1853delinsGC (aka c.1852_1853AA>GC, Lys618Ala). Leeds – found in 4 out of ~400 patients DMuDB – entered Birmingham (x6), Leeds (x1), Dundee (x4) – unclassified Newcastle consider it non-pathogenic ~50 entries in InSIGHT (LOVD) database ~40 entries in New Foundland MMR database

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MLH1 c.1852_1853delinsGC (aka c.1852_1853AA>GC, Lys618Ala)

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  1. MLH1 c.1852_1853delinsGC (aka c.1852_1853AA>GC, Lys618Ala) • Leeds – found in 4 out of ~400 patients • DMuDB – entered Birmingham (x6), Leeds (x1), Dundee (x4) – unclassified • Newcastle consider it non-pathogenic • ~50 entries in InSIGHT (LOVD) database • ~40 entries in New Foundland MMR database • Described at least once in literature (and once in correspondence with IF) in trans with a truncating mutation in non-Turcot/mismatch repair cancer syndrome associated with bi-allelic loss • Some evidence that Lys618Ala reduces MLH1/PMS2 dimerisation by a large degree (Guerrette et al 1999, PMID 10037723) • Yeast functional studies (various methods; DME, 2-hybrid) maintain MMR, sometimes at a sub-normal level (Takahashi at al 2007, Kondo et al 2003, PMIDs 17510385 & 12810663) • Large population study found it at a higher % in healthy individuals than in CRC (familial & sporadic; Christensen et al 2008 PMID1847406) • Consensus? INCLUDE CMGS POLICY IN BP GUIDELINES?

  2. Duplications; how do we report them? • Patient: Ca uterus & melanoma. FH uterine, bladder & colon Ca. • Patient & affected sister (Ca uterus) duplication of MSH2 ex1-6 by MLPA (confirmed by 2nd kit); no further muts in MLH1, MSH2, MSH6. • Endometrial carcinoma – MSI-H & loss of MSH2 & MSH6 on IHC (poor staining for MSH6 on normal control tissue). • Possible production of functional transcriptional element?

  3. Duplications; how do we report them? • Triplication/homozygous duplication • Patient: Ca bowel @ 30, Amsterdam +ve on maternal side, no known FH on paternal side (father died glioblastoma @ 60). • 4 copies of MLH1 ex5-8 detected – apparently at least 2 of which are contiguous (ascertained by using exon 8F and exon 5R primers & long PCR); possibility of 3 contiguous copies on one allele • Not apparently MMRCS/Turcot syndrome-type clinical picture, despite early onset of CRC. • Found nothing similar in literature – any ideas/shared experience? • Should/will there be something in the BPG regarding MMRCS?

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