NM_003977.4(AIP):c.805_825dup (p.Phe269_His275dup) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Oct 17, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001027111.1

Allele description [Variation Report for NM_003977.4(AIP):c.805_825dup (p.Phe269_His275dup)]

NM_003977.4(AIP):c.805_825dup (p.Phe269_His275dup)

Gene:
AIP:aryl hydrocarbon receptor interacting protein [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
11q13.2
Genomic location:
Preferred name:
NM_003977.4(AIP):c.805_825dup (p.Phe269_His275dup)
HGVS:
  • NC_000011.10:g.67490805_67490825dup
  • NG_008969.1:g.12772_12792dup
  • NM_001302959.1:c.628_648dup
  • NM_001302960.2:c.797_817dup
  • NM_003977.4:c.805_825dupMANE SELECT
  • NP_001289888.1:p.Phe210_His216dup
  • NP_001289889.1:p.Leu266_Pro272dup
  • NP_003968.3:p.Phe269_His275dup
  • LRG_460t1:c.805_825dup
  • LRG_460:g.12772_12792dup
  • NC_000011.9:g.67258273_67258274insACTTCAAGCGGGGCAAGGCCC
  • NC_000011.9:g.67258276_67258296dup
  • NM_003977.2:c.805_825dupTTCAAGCGGGGCAAGGCCCAC
Links:
dbSNP: rs267606578
NCBI 1000 Genomes Browser:
rs267606578
Molecular consequence:
  • NM_001302959.1:c.628_648dup - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001302960.2:c.797_817dup - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_003977.4:c.805_825dup - inframe_insertion - [Sequence Ontology: SO:0001821]
Observations:
1

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001189617Ambry Geneticscriteria provided, single submitter
Pathogenic
(Oct 17, 2019)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families.

Igreja S, Chahal HS, King P, Bolger GB, Srirangalingam U, Guasti L, Chapple JP, Trivellin G, Gueorguiev M, Guegan K, Stals K, Khoo B, Kumar AV, Ellard S, Grossman AB, Korbonits M; International FIPA Consortium..

Hum Mutat. 2010 Aug;31(8):950-60. doi: 10.1002/humu.21292.

PubMed [citation]
PMID:
20506337
PMCID:
PMC3065644

Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients.

Cazabat L, Bouligand J, Salenave S, Bernier M, Gaillard S, Parker F, Young J, Guiochon-Mantel A, Chanson P.

J Clin Endocrinol Metab. 2012 Apr;97(4):E663-70. doi: 10.1210/jc.2011-2291. Epub 2012 Feb 8.

PubMed [citation]
PMID:
22319033
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV001189617.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)

Description

The c.805_825dup21 pathogenic mutation (also known as p.F269_H275dup), located in coding exon 6 of the AIP gene, results from an in-frame duplication of 21 nucleotides at nucleotide positions 805 to 825. This results in the duplication of 7 extra residues (FKRGKAH) between codons 269 and 275. This duplication has been reported in multiple individuals with familial isolated pituitary adenomas (FIPA) resulting in gigantism and/or acromegaly, although some carriers in these families remained unaffected (Leontiou CA et al. J. Clin. Endocrinol. Metab. 2008 Jun;93(6):2390-401; Igreja S. et al. Hum. Mutat. 2010 Aug;31(8):950-60; Salvatori R. et al. Eur. J. Endocrinol. ​2017 Sep;177(3):257-266; Cazabat L et al. J. Clin Endocrinol. Metab. 2012 Apr;97(4):E663-70). One affected individual also developed a GIST (Hernandez-Ramire LC et al. J. Clin. Endocrinol. Metab. 2015 Sep;100(9):E1242-54). Authors of one study proposed replication slipage as the mechanism for this duplication and report this as an English founder mutation due to a shared haplotype around AIP in affected, unrelated individuals (Salvatori R. et al. Eur. J. Endocrinol. ​2017 Sep;177(3):257-266). In addition, co-immunoprecipitation with this AIP mutant and HSP90 showed lack of interaction between these two proteins, resulting in reduced protein stability (Salvatori R. et al. Eur. J. Endocrinol. 2017 Sep;177(3):257-266). Furthermore, this variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Of note, this mutation is also referred to as c.794_823dup (p.A247_H275ins10) in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2021

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