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HNPCC case study

HNPCC case study. Miranda Durkie Sheffield Diagnostic Genetics Service. Referral & testing. Referral from 26yr old lady, VB, Indian origin, sigmoid colon cancer aged 21 plus further polyps & tubullovillous adenoma aged 26 FH of bowel cancer in maternal uncle and grandmother

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HNPCC case study

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  1. HNPCC case study Miranda Durkie Sheffield Diagnostic Genetics Service

  2. Referral & testing • Referral from 26yr old lady, VB, Indian origin, sigmoid colon cancer aged 21 plus further polyps & tubullovillous adenoma aged 26 • FH of bowel cancer in maternal uncle and grandmother • MLH1/MSH2 testing requested • Found p.Trp714X, in ex19 of MLH1 – previously reported several times • Also found novel p.Tyr97Cys in ex3 of MLH1

  3. Evidence for p.Tyr97Cys UV 1 • Highly conserved nucleotide (score 1.0) • Highly conserved aa (to yeast) • Tyr or Phe in all species including paralogues (38 proteins in total) • ATP-binding region • p.Gly98Asp found in very large local family and segregates according to disease in at least 8 affected and several unaffected • p.Gly98Arg & p.Gly98Ser also reported

  4. Evidence for p.Tyr97Cys UV 2 • SIFT score = 0.00 • Polyphen = probably damaging (38 proteins) • Align GVGD = Class C55 (C65 most likely) • SNPs3D score = -2.39 (67 proteins) • CanPredict = Likely Cancer (based on SIFT PFam and GOSS) • Panther Pdel score = 0.99

  5. Report for VB • Reported as p.[Tyr97Cys(+)Trp714X] • p.Trp714X mutation previously reported in patients with HNPCC • “The p.Tyr97Cys putative mutation predicted to be pathogenic by 5 in silico tools, however without functional studies we cannot be certain of it’s pathogenicity” • “Analysis of other family members, particularly parents, is recommended to determine phase of these 2 variants in order to determine risk to other family members. Analysis of other affected family members would also aid interpretation of these results”

  6. GC appointment and further testing • All other family members including parents and other affected individuals are in India • She is married to her 1st cousin (related on maternal side) • Predictive testing on husband, MB, showed he had inherited p.Tyr97Cys putative mutation alone

  7. Report for Husband • “This variant has not been detected in individuals with HNPCC and without functional studies we cannot be certain of it’s significance.” • “Therefore the risk of HNPCC to MB cannot be determined. Testing of other affected family members may help to clarify his risk”.

  8. Updated report for VB • “It is therefore likely that the p.Tyr97Cys, c.290A>G novel putative mutation and the p.Trp714X, c.2141G>A mutation are located on different chromosomes in VB. This has implications for other family members and future offspring”.

  9. Pedigree

  10. Follow up GC appointment • Family history of CRC on BOTH sides • VB doesn’t speak English • MB needs colonoscopy (still awaiting appt) • MB very keen to have children • Discussed possible outcomes in offspring • MB wants egg donation but still 50% risk of inheriting p.Tyr97Cys • Referred to Fertility Centre but several issues (e.g. 6 cycles of chemo in VM)

  11. Discussion points • Full vs partial DNA sequencing/checking • 10 families with biallelic MLH1 mutations reported • Majority have very early onset haematological and brain malignancies • 3 reported cases with residual MMR activity and gastrointestinal tumours in 3nd -4th decade • Therefore phenotype of VB fits with residual MMR activity • ?due to residual activity of p.Tyr97Cys or possibly p.Trp714X as only loses last 43 aa’s so may not be subject to NMD • phenotype for offspring?

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