N54: Characterisation Of Mismatch Repair Variants Submitted To The International Mismatch Repair Consortium (IMRC)

J. Reece1, D. Buchanan1, 2, G. Lee1, J. P. Plazzer3, K. Mahmood4, B. Pope4, M. Clendenning2, A. Win1, 5, R. Haile6, G. Möslein7, F. Macrae3, 8, 9, M. Jenkins1, 5

1 –  Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia. 2 – Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia. 3 – Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia. 4 – Melbourne Bioinformatics, The University of Melbourne, Parkville, Victoria, Australia. 5 – The University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia. 6 – Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. 7 – Helios St. Josefs-Hospital, Bochum-Linden, Germany. 8 – Genetic Medicine and Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, Victoria, Australia. 9 – Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, Victoria, Australia.

 

Aim: The IMRC contains data from 4624 Lynch families from 22 countries. We examined the geographical distribution of MMR mutations.

Method: Pedigree data includes: country, MMR mutation and cancer history. Frequency of each variant was calculated by geographical region.

Results: Of the 1578 unique MMR variants (MLH1=568, MSH2=582, MSH6=293, PMS2=135), the two most commonly reported variants were:

Gene: Variant (number of families with variant):

MLH1:

North America: c.350C>T (26), c.1852_1854del (22)

Europe: c.1489dup (48), c.676C>T (28)

South America: c.350C>T (6), c.1276C>T (6)

Asia: c.381_453del (11), c.1852_1854del (4)

Australasia: c.1852_1854del (12), c.350C>T (10)

MSH2:

North America: c.942+3A>T (88), c.(?_-125)_1076+?del (67)

Europe: c.942+3A>T (130), c.1165C>T (25), c.1786_1788del (25)

South America: c.942+3A>T (2), c.1077-?_1276+?del (2)

Asia: c.1457_1460del (19), c.942+3A>T (5)

Australasia: c.942+3A>T (16), c.2502_2508del (8)

MSH6:

North America: c.3261dup (18), c.2731C>T (12)

Europe: c.3261dup (29), c.2731C>T (16)

South America: c.1519dup (2)

Asia: c.3261dup (2)

Australasia: c.3261dup (7), c.1571dup (5)

PMS2:

North America: c.137G>T (28), c.736_741delins11 (19)

Europe: c.736_741delins11 (14), c.1882C>T (6)

South America: c.2186_2187del (2), c.2192_2196del (2)

Asia: c.1572del (2), c.861_864del (2)

Australasia: c.736_741delins11 (11), c.989-296_1144+706del (4)

Conclusion: Some variants are frequently identified across geographical regions but heterogeneous distribution was found for other common variants. The IMRC has the potential to increase our understanding of the geographic distribution of Lynch syndrome.

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