SH2 domain proteins have been identified as altered in hereditary or sporadic human diseases.  Known mutations in the genes for 18 distinct SH2 domain proteins contribute to human disorders, including cancers and leukemias, developmental disorders, diabetes, and immunodeficiencies.  These can arise from either loss- or gain-of-function mutations in SH2 domains.

Additional information on SH2 domain mutations can be found at:
Lappalainen I et al., Genome wide analysis of pathogenic SH2 domain mutations.  Proteins.  2008 Aug;72(2):779-92.

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Gene NameSummary of MutationsPhenotypeSource
Gene NameSummary of MutationsPhenotypeSource
ABL1 t(9;22) translocation results in fusion with the BCR gene Chronic myelogeneous leukemia (CML), acute lymphoblastic leukemia (ALL), myelogenous leukemia (AML) (de Klein et al., 1982) 
ABL2 t(1;12)(q25;p13) translocation with ETV6/TEL Acute myeloid leukemia  (Cazzaniga et al., 1999) 
BLNK Complete loss or drastic reduction of expression due to incorporation of alternative exons Pre-B-cell Acute Lymphoblastic Leukemia (ALL) (Jumaa et al., 2003) 
BLNK Base pair substitution of a splice donor site result in reduction of loss of BLNK transcripts Human Immundeficiency  (Minegishi et al., 1999) 
BTK Missense mutations, deletions or slice site mutations  X-linked agammaglobulinemia (XLA)  (Rawlings et al., 1993) 
CBL Translocation with MLL Acute myeloid leukemia (Fu et al., 2003) 
CBL t(4;11)(q21;q23) Acute leukemia (Savage et al., 1991) 
CBL t(11;22)(q23;q12) Ewing sarcoma  (Savage et al., 1991) 
CISH Five single-nucleotide polymorphisms (SNPs) (at positions -639, -292, -163, +1320, and +3415  Susceptibility to diseases caused by diverse infectious pathogens (Khor CC et al., 2010) 
CRK Deletions of 17p13.3 Isolated lissencephaly sequence (ILS) to Miller-Dieker syndrome (MDS)  (Cardoso et al., 2003) 
ITK t(5;9)(q33;q22) translocation to SYK Peripheral T-cell lymphoma (Streubel et al., 2005) 
JAK2 t(9;12)(p24;p13) fusion with TEL, results in an constitutive kinase Acute lymphoblastic leukemia  (Lacronique et al., 1997) 
JAK2 t(9;15;12)(p24;q15;p13) fusion with TEL and ETV6  Chronic myelogenous leukemia  (Peeters et al., 1997) 
JAK3 Nucleotide insertion, substitution or deletion resulting in a frame shift or premature termination.  SCID, lymphopenia (Russell et al., 1995) 
LCK Translocation of the t(1;7)(p34;q34) that fuses LCK and TCRB T-cell acute lymphoblastic leukemia (T-cell ALL)  (Burnett et al., 1991) 
LCK Decrease expression of p56(lck), likely due to alternative splicing of exon 7  SCID (Goldman et al., 1998) 
LNK 5 bp deletion and missense mutation leading to a premature stop codon and loss of the pleckstrin homology (PH) and SH2 domains; missense mutation (E208Q) in the PH domain Myeloproliferative neoplasms (MPNs) (OH ST et al., 2010) 
LYN D189Y Escapes from antiestrogens in a subset of ER+ breast cancers Schwarz et al., 2014 
PLCG2  hypermorphic missense mutation c.2120C>A (p.Ser707Tyr) Autoinflammatory disease Zhou et al., 2012 
PTPN11 Missense mutation in exon 7, 12 and 13 Multiple lentigines (ML)/Leopard Syndrome (LS)  (Digilio et al., 2002) 
PTPN11 95% of mutations are in exon 3 or a defect in exon 13 affecting the protein tyrosine phosphatase domain resulting in a gain of function Juvenile Myelomonocytic Leukemia (JMML) (Tartaglia et al., 2003) 
PTPN11 Missense mutations altering amino acids D61 at the N-SH2 domain, resulting in gain of function Noonan Syndrome  (Tartaglia et al., 2001) 
RASA1 Nonsense mutations within the SH2 domain  Basal cell carcinoma  (Friedman et al., 1993) 
RASA1 A 2bp deletion results in a frameshift and a premature stop codon; a missense mutation in the PH domain  Capillary malformation-arteriovenous malformation (Eerola et al., 2003) 
SH2D1A Mutations or deletions truncating the the protein to not fold and function correctly X-linked lymphoproliferative syndrome (XLP)  (Sayos et al., 1998) 
SH3BP2 Point mutations in exon 9 affect 3 amino acids within the 6 amino acid sequence (RSPPDG) Cherubism  (Ueki et al., 2001) 
SHIP2 Homozygous A630P mutation  Growth hormone insensitivity with immunodeficiency  (Kofoed et al., 2003) 
SHIP2 Mutation or Deletions, SNPs Type 2 Diabetes, hypertension (Marion et al., 2002) 
SRC Truncating mutation in the SRC codon 531  Advanced Colon Cancer  (Irby et al., 1999) 
STAT1 Nucleotide substitutions, homozygous deletions generating a premature stop codon  Susceptibility to mycobacterial and viral disease  (Dupuis et al., 2001) 
STAT3  Y640F in 13 (17%), D661V in 7 (9%), D661Y in 7 (9%), and N647I in 3 (4%) Large granular lymphocytic leukemia (Koskela et al., 2012) 
STAT5B t(15;17)(q11.2; q21.1) translocation with RARA Acute promyeloyctic leukemia (APL)  (Arnould et al., 1999) 
SYK t(9;12)(q22;p12) translocation with TEL Myelodysplastic syndrome (MDS) (Kuno et al., 2001) 
SYK t(5;9)(q33;q22) translocation with ITK Peripheral T-cell lymphoma (Streubel et al., 2005) 
ZAP70 A single base substitution mutation in a splice acceptor site  SCID (T-cell defect)  (Elder et al., 1994) 
ZAP70 A single base substitution mutation in a splice acceptor site  SCID (T-cell defect)  (Chan et al., 1994)  
Showing 36 items