We have reported six cases of de novo germline mutation in MMR genes (two MLH1, three MSH2, and one MSH6) from the Colon Cancer Family Registry. This is the first report, to our knowledge, on a case series of de novo germline mutation in MMR genes.
All specific de novo mutations except one that we observed in this study were different from the previously reported de novo mutations in MLH1
mutation in exon 5: c.942+3A→T p. Val265_Gln314del that we observed in proband 4 was the same mutation reported by Desai et al28
in which the 942+3 mutation was recognised as being relatively common in Lynch syndrome series around the world. They estimated that this type of de novo mutation accounted for 11% of all known pathogenic MSH2
mutations. Because haplotype sharing across families was not found, the authors concluded that this mutation occurred de novo with a relatively high frequency. They hypothesised that it may arise as a consequence of misalignment of DNA strands at replication. Indeed, this mutation was found to be one of the six de novo mutation carriers in our series.
If a disease-causing mutation found in the proband cannot be detected in the DNA of either parent, three possible explanations need to be considered: non-paternity/non-maternity, germline mosaicism in a parent, or that the mutation is de novo. Non-paternity/non-maternity could be confidently excluded as a possible explanation in each of the six de novo mutation probands. However, we did not have the opportunity to test multiple tissues in our patients and their parents for the mutation and, therefore, could not rule out the possibility that these mutations were early postzygotic mutations or due to parental germline mosaicism.
We have estimated the proportion of MMR gene mutation carriers that have de novo mutations to be between 1 in 100 (0.9%) and 1 in 20 (5.0%). This is comparable to previous small studies which estimated proportions of 1% (1/114)23
or 2% (1/47).21
De novo germline mutations in MMR genes, therefore, appear to be rare in contrast to other hereditary CRC syndromes: 11–25% in the adenomatous polyposis coli (APC
) gene mutations that cause familial adenomatous polyposis (MIM 175100),13–16
25–50% in the LKB1
gene mutations that cause Peutz-Jeghers syndrome (MIM 175200),17,18
and ~25% in BMPR1A
mutations that cause juvenile polyposis syndrome (MIM 174900).18,19
We observed that the average age of onset for CRC in the de novo carriers was younger than for the non-de novo carriers. Overreliance on family history of cancer—for example, the Amsterdam criteria29
—to guide MMR gene mutation testing will contribute to the under-diagnosis of Lynch syndrome resulting from de novo mutations. None of the six de novo mutation carriers had a family history that met the Amsterdam criteria. A proposed alternative approach25
uses a tumour based strategy that has been demonstrated to identify persons with Lynch syndrome more efficiently. All the CRC tumours from the six probands with de novo mutations lacked the MMR protein corresponding to the mutated gene. Recognition of the presence of de novo mutations in three different MMR genes and a relatively high frequency of de novo mutations in population based probands supports the application of tumour testing for loss of MMR function to identify people without a family history, but at high risk of having a pathogenic MMR gene mutation.