Supplemental Table 1.
Article Title: Juvenile Myelomonocytic Leukemia Due to a Germline CBL Y371C Mutation: 35-Year Follow-up of a Large Family
Journal Name: Human Genetics
Author Names and Affiliations:
Anand Pathak1, Alexander Pemov1, Mary Lou McMaster2, Ramita Dewan1, Sarangan Ravichandran3, Evgenia Pak4, Amalia Dutra4, Hyo Jung Lee5, Aurelie
Vogt5, Xijun Zhang5, Meredith Yeager5, Stacie Anderson6, Martha Kirby6, NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing
Working Group, Neil Caporaso2, Mark H. Greene1, Lynn Goldin2, Douglas R. Stewart1
1
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;
2
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;
3
Frederick National Laboratory for Cancer Research; Simulation, Analysis, and Mathematical Modeling Group Advanced Biomedical Computing Center,
Frederick, MD, USA;
4
Cytogenetic and Microscopy Core, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD,
USA;
5
Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD,
USA;
6
Flow Cytometry Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
NCI DCEG Cancer Sequencing Working Group: Bari Ballew, Stephen J. Chanock, Alisa M. Goldstein, Allan Hildesheim, Nan Hu, Maria Teresa Landi,
Jennifer Loud, Phuong L. Mai, Lisa Mirabello, Lindsay Morton, Dilys Parry, Melissa Rotunno, Sharon A. Savage, Philip R. Taylor, Geoffrey S. Tobias,
Margaret A. Tucker, Jeannette Wong, Xiaohong R. Yang, Guoqin Yu
NCI DCEG Cancer Genomics Research Laboratory: Sara Bass, Joseph Boland, Laurie Burdette, Salma Chowdhury, Michael Cullen, Casey Dagnall, Herbert
Higson, Amy A. Hutchinson, Kristine Jones, Sally Larson, Kerrie Lashley, Hyo Jung Lee, Wen Luo, Michael Malasky, Michelle Manning, Jason Mitchell, David
Roberson, Aurelie Vogt, Mingyi Wang
Key words: JMML, familial, CBL, germline mutation, whole-exome sequencing
Correspondence to: DRS (9609 Medical Center Drive Rm 6E450, Bethesda, MD, 20892; Tel: 240-276-7238; Fax: 240-276-7836; drstewart@mail.nih.gov)
Supplemental Table 1. World Health Organization Clinical Criteria for Juvenile Myelomonocytic Leukemia.*
Laboratory Criteria
Persistent peripheral blood
monocytosis >1x109/L
IV.2
1600/µL (9/2010); 1500/µL
(3/2011); 1300/µL (11/2013)
III.12
1904/µL (6/1993); 3800/µL
(7/2014); 1,500/µL (9/2014)
III.1
924/µL (2/1949); 820 (12/2012)
Blasts are <20% in peripheral blood
and bone marrow
2% peripheral blood, 8% bone
marrow
< 2% blasts bone marrow
2 % blasts peripheral blood
No Philadelphia chromosome
No Philadelphia chromosome
No Philadelphia chromosome
No Philadelphia chromosome
Hemoglobin F increased for age
6.70% (>1.0% abnormal)
No documentation of elevation
No documentation of elevation
Immature granulocytes in the
peripheral blood
Yes
Yes
Yes
WBC count >10x109/L.
Yes
Yes
Yes
Clonal chromosomal abnormality
(may be monosomy 7)
No
No
No
GM-CSF hypersensitivity of
myeloid progenitors in vitro
N/A
N/A
N/A
Further Criteria
* To meet diagnostic criteria, a patient must meet all three laboratory criteria and fulfill at least two further criteria.
Table 2. In Silico Predictions of CBL Y371C Pathogenicity
PREDICTION PROGRAM
SCORE
INTERPRETATION
0
Deleterious
POLYPHEN 2 HumDiv
0.999
Probably Damaging
POLYPHEN 2 HumVar
1.000
Probably Damaging
MUTATION TASTER
0.999999
Disease Causing
MUTATION ASSESSOR
2.35
Medium
FATHMM--MISSENSE
-4.09
Damaging
FATHMM--CANCER
-5.39
Cancer
CADD SCALED C-SCORE
16.7
Between top 10% (10) and top 1% (20)
SIFT