Submissions for variant NM_003977.4(AIP):c.967C>T (p.Arg323Trp)

gnomAD frequency: 0.00006  dbSNP: rs188965257

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564964	SCV000672446	likely benign	Hereditary cancer-predisposing syndrome	2023-03-22	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	RCV001040402	SCV001203974	uncertain significance	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 323 of the AIP protein (p.Arg323Trp). This variant is present in population databases (rs188965257, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with nonfunctioning pituitary adenoma (PMID: 24050928). ClinVar contains an entry for this variant (Variation ID: 485063). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AIP protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001526825	SCV001737489	uncertain significance	Familial isolated pituitary adenoma	2021-05-13	criteria provided, single submitter	clinical testing	The AIP c.967C>T (p.Arg323Trp) missense change has a maximum subpopulation frequency of 0.057% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-67258438-C-T?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, but these predictions have not been confirmed by functional studies. This variant has been reported in a male with a nonfunctioning pituitary adenoma whose tumor showed loss of heterozygosity (PS4_supporting; PMID: 24050928). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PS4_supporting.
GeneDx	RCV001040402	SCV004023987	uncertain significance	not provided	2023-02-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a pituitary adenoma that displayed loss of heterozygosity (Cai et al., 2013); This variant is associated with the following publications: (PMID: 24050928, 27093186)