Submissions for variant NM_003977.4(AIP):c.733G>A (p.Glu245Lys)

gnomAD frequency: 0.00012  dbSNP: rs150645662

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001026294	SCV001188644	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	clinical testing	The p.E245K variant (also known as c.733G>A), located in coding exon 5 of the AIP gene, results from a G to A substitution at nucleotide position 733. The glutamic acid at codon 245 is replaced by lysine, an amino acid with similar properties. This alteration was identified in the germline of an individual with a prolactinoma that did not exhibit loss-of-heterozygosity for AIP (Cai F et al. Eur. J. Endocrinol., 2013 Dec;169:867-84). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001105892	SCV001262906	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.
Invitae	RCV001231533	SCV001404059	uncertain significance	not provided	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 245 of the AIP protein (p.Glu245Lys). This variant is present in population databases (rs150645662, gnomAD 0.05%). This missense change has been observed in individual(s) with a prolactinoma (PMID: 24050928). ClinVar contains an entry for this variant (Variation ID: 826974). 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 not expected to disrupt AIP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect AIP function (PMID: 34588620). 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.
Sema4, Sema4	RCV001026294	SCV002535453	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-04	criteria provided, single submitter	curation
GeneDx	RCV001231533	SCV003926355	uncertain significance	not provided	2022-11-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: variant did not affect RET signaling (Garcia-Rendueles et al., 2021); Observed in a patient with a prolactinoma that did not display loss of heterozygosity (Cai F et al., 2013); This variant is associated with the following publications: (PMID: 34588620, 24050928)
Baylor Genetics	RCV001105892	SCV004195283	uncertain significance	Somatotroph adenoma	2023-10-16	criteria provided, single submitter	clinical testing