Submissions for variant NM_000038.6(APC):c.532T>A (p.Phe178Ile)

gnomAD frequency: 0.00001  dbSNP: rs1060503344

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003766590	SCV000552702	uncertain significance	Familial adenomatous polyposis 1	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 178 of the APC protein (p.Phe178Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 411510). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002492	SCV001160445	uncertain significance	not specified	2019-04-05	criteria provided, single submitter	clinical testing	The APC c.532T>A; p.Phe178Ile variant (rs1060503344), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 411510). This variant is found on a single chromosome (1/248956) in the Genome Aggregation Database, indicating it is not a common polymorphism. The phenylalanine at codon 178 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, although the majority of pathogenic APC variants are truncating nonsense or frameshift variants (Kerr 2013, InSiGHt database). Due to limited information, the clinical significance of the p.Phe178Ile variant is uncertain at this time. References: Link to InSiGHt database: https://www.insight-group.org/syndromes/adenomatous-polyposis/ Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43.
Color Diagnostics, LLC DBA Color Health	RCV001180356	SCV001345273	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with isoleucine at codon 178 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in families affected with familial adenomatous polyposis (Mayordomo et al. 2020, https://doi.org/10.1007/s10689-019-00150-8). This variant has been identified in 1/248956 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001753909	SCV002007417	uncertain significance	not provided	2019-09-26	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV001180356	SCV002535619	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-26	criteria provided, single submitter	curation
Ambry Genetics	RCV001180356	SCV002643181	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-22	criteria provided, single submitter	clinical testing	The p.F178I variant (also known as c.532T>A) is located in coding exon 5 of the APC gene. The phenylalanine at codon 178 is replaced by isoleucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 5. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV002525612	SCV004202221	uncertain significance	Familial adenomatous polyposis 1	2023-07-03	criteria provided, single submitter	clinical testing