Unaffected germline genetic testing for individuals at high risk of Lynch Syndrome – results from first 3 years in practice

Demetra Georgiou1, Hannah Shipman 2, Cheryl Berlin 2, Angela F Brady 2, Kevin J Monahan 3,4, Huw J W Thomas 3,4

1 Guys’ and St Thomas’ NHS Foundation Trust, London, United Kingdom. 2 North West London Healthcare NHS Trust, London, United Kingdom. 3 St Mark’s Hospital, London, United Kingdom. 4 Imperial College Healthcare NHS Trust, London, United Kingdom


Lynch Syndrome (LS) is one of the most common hereditary causes of colorectal cancer. Recent universal screening programmes have improved diagnostic rate through reflex tumour Mismatch Repair (MMR) screening, utilising Immunohistochemistry or Microsatellite Instability tests. LS assessment in cases prior to reflex screening is possible, pending availability of tumour sample.


Tumour availability is a limitation in the assessment of these cases as: regulations in the UK prohibit retention of specimens for longer than 30 years; samples may be inadequate; proband samples may be abroad. As such, at-risk individuals attending a genetics clinic may not be offered genetic investigations.


We implemented an unaffected LS testing policy for kindred’s fulfilling Modified Amsterdam Criteria where testing in an affected relative was not possible. First degree relatives of probands fulfilling such criteria have ~22-26% risk of carrying a pathogenic variant in the MMR genes.


To date, we offered testing to 15 individuals. Five reports are pending, eight indicate no pathogenic variants. A pathogenic MLH1 and MSH2 variant were found in two patients who were offered screening and management options. Screening recommendations were reviewed in MDT meetings. In line with the new UK genetic test directory, we suggest consideration of unaffected testing to benefit individuals at high risk of LS to tailor colonoscopy surveillance; risk management options and cascade testing.