Submissions for variant NM_003977.4(AIP):c.807C>T (p.Phe269=)

gnomAD frequency: 0.00055  dbSNP: rs139407567

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000034108	SCV000373583	likely benign	Somatotroph adenoma	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Ambry Genetics	RCV000571925	SCV000672424	likely benign	Hereditary cancer-predisposing syndrome	2020-03-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000951118	SCV001097483	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000034108	SCV001483039	uncertain significance	Somatotroph adenoma	2018-12-21	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 18381572, 25184284]
GeneDx	RCV000951118	SCV001772730	likely benign	not provided	2019-07-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 2200621, 26186299, 21753072, 17609395, 28220018, 23038625, 18381572, 25184284, 20506337, 18410548)
Sema4, Sema4	RCV000571925	SCV002535458	likely benign	Hereditary cancer-predisposing syndrome	2021-06-23	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003952391	SCV004770356	likely benign	AIP-related disorder	2023-08-25	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
GeneReviews	RCV000034108	SCV000058038	not provided	Somatotroph adenoma		no assertion provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000951118	SCV001548583	likely benign	not provided		no assertion criteria provided	clinical testing	The AIP p.F269F variant was identified in 5 individuals with pituitary adenoma, acromegaly, gigantism, or macroadenoma, however the variant was also identified in unaffected family members (DeSousa_2017_PMID:28220018; Preda_2014_PMID:25184284; Oriola_2012_PMID:23038625; Igreja_2010_PMID:20506337). Functional studies reveal that individuals and in vitro models with this variant have decreased AIP mRNA expression compared to control (Igreja_2010_PMID:20506337). The variant was identified in dbSNP (ID: rs139407567), LOVD 3.0 and ClinVar (classified as uncertain significance by Ambry Genetics and as likely benign by Illumina and Invitae). The variant was identified in control databases in 154 of 280240 chromosomes at a frequency of 0.0005495 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 112 of 127076 chromosomes (freq: 0.000881), South Asian in 21 of 30602 chromosomes (freq: 0.000686), Other in 4 of 7176 chromosomes (freq: 0.000557), Latino in 10 of 35398 chromosomes (freq: 0.000283), African in 6 of 24736 chromosomes (freq: 0.000243) and European (Finnish) in 1 of 25074 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, or East Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000951118	SCV001741536	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000951118	SCV001958502	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000951118	SCV001969490	uncertain significance	not provided		no assertion criteria provided	clinical testing