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UniProtKB/Swiss-Prot P07949: Variant p.Met918Thr

Proto-oncogene tyrosine-protein kinase receptor Ret
Gene: RET
Variant information

Variant position:  918
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  LP/P [Disclaimer]
The variants are classified into three categories: LP/P, LB/B and US.
  • LP/P: likely pathogenic or pathogenic.
  • LB/B: likely benign or benign.
  • US: uncertain significance

Residue change:  From Methionine (M) to Threonine (T) at position 918 (M918T, p.Met918Thr).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and hydrophobic (M) to medium size and polar (T)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -1
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Variant description:  In MEN2B and MTC; sporadic form; somatic mutation; also found in a patient with renal agenesis.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  918
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  1114
The length of the canonical sequence.

Location on the sequence:   DVYEEDSYVKRSQGRIPVKW  M AIESLFDHIYTTQSDVWSFG
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         DVYEEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFG

Mouse                         DVYEEDSYVKKSKGRIPVKWMAIESLFDHIYTTQSDVWSFG

Rat                           DVYEEDSYVKKSKGRIPVKWMAIESLFDHIYTTQSDVWSFG

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 29 – 1114 Proto-oncogene tyrosine-protein kinase receptor Ret
Chain 708 – 1017 Soluble RET kinase fragment
Topological domain 658 – 1114 Cytoplasmic
Domain 724 – 1016 Protein kinase
Modified residue 900 – 900 Phosphotyrosine; by autocatalysis
Modified residue 905 – 905 Phosphotyrosine; by autocatalysis
Mutagenesis 708 – 1114 Missing. Loss of induced cell death, but increased cell aggregation.


Literature citations

Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours.
Eng C.; Smith D.P.; Mulligan L.M.; Nagai M.A.; Healey C.S.; Ponder M.A.; Gardner E.; Scheumann G.F.; Jackson C.E.; Tunnacliffe A.; Ponder B.A.J.;
Hum. Mol. Genet. 3:237-241(1994)
Cited for: VARIANT MEN2B THR-918;

A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.
Hofstra R.M.W.; Landsvater R.M.; Ceccherini I.; Stulp R.P.; Stelwagen T.; Luo Y.; Pasini B.; Hoeppener J.W.M.; Ploos van Amstel H.K.; Romeo G.; Lips C.J.M.; Buys C.H.C.M.;
Nature 367:375-376(1994)
Cited for: VARIANT MEN2B THR-918;

Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B.
Carlson K.M.; Dou S.; Chi D.; Scavarda N.; Toshima K.; Jackson C.E.; Wells S.A. Jr.; Goodfellow P.J.; Donis-Keller H.;
Proc. Natl. Acad. Sci. U.S.A. 91:1579-1583(1994)
Cited for: VARIANT MEN2B THR-918;

Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B.
Kitamura Y.; Scavarda N.; Wells S.A. Jr.; Jackson C.E.; Goodfellow P.J.;
Hum. Mol. Genet. 4:1987-1988(1995)
Cited for: VARIANT MEN2B THR-918; VARIANT TYR-922;

Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations.
Kambouris M.; Jackson C.E.; Feldman G.L.;
Hum. Mutat. 8:64-70(1996)
Cited for: VARIANTS MEN2A; VARIANT MTC ASP-768; VARIANT MEN2B THR-918;

Renal aplasia in humans is associated with RET mutations.
Skinner M.A.; Safford S.D.; Reeves J.G.; Jackson M.E.; Freemerman A.J.;
Am. J. Hum. Genet. 82:344-351(2008)
Cited for: VARIANTS THR-198; ALA-376; HIS-394; ILE-778; SER-894; THR-918; LEU-1049 AND SER-1067; POSSIBLE INVOLVEMENT IN RENAL AGENESIS; CHARACTERIZATION OF VARIANTS THR-198; ALA-376; HIS-394; ILE-778; SER-894; LEU-1049 AND SER-1067;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.