Submissions for variant NM_000038.6(APC):c.5189C>T (p.Ser1730Phe)

gnomAD frequency: 0.00001  dbSNP: rs864622256

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003468936	SCV000259864	uncertain significance	Familial adenomatous polyposis 1	2023-09-29	criteria provided, single submitter	clinical testing	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. 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 APC protein function. ClinVar contains an entry for this variant (Variation ID: 219793). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1730 of the APC protein (p.Ser1730Phe).
Ambry Genetics	RCV000216423	SCV000276985	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	The p.S1730F variant (also known as c.5189C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 5189. The serine at codon 1730 is replaced by phenylalanine, an amino acid with highly dissimilar properties. In a case control study, this alteration was reported in 0/691 unrelated North American patients with colorectal adenomas and 1/969 matched healthy controls (Azzopardi D et al. Cancer Res. 2008 Jan; 68(2):358-63). This amino acid position is well 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.
GeneDx	RCV000236704	SCV000293120	uncertain significance	not provided	2018-08-09	criteria provided, single submitter	clinical testing	This variant is denoted APC c.5189C>T at the cDNA level, p.Ser1730Phe (S1730F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). This variant was observed in at least one reportedly healthy individual (Azzopardi 2008). APC Ser1730Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). APC Ser1730Phe is located within the Beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether APC Ser1730Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000216423	SCV000681713	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-19	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 1730 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature but has been found in one health control individual (PMID 18199528). This variant has been identified in 1/250488 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.
Sema4, Sema4	RCV000216423	SCV002535076	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-04	criteria provided, single submitter	curation
Baylor Genetics	RCV003468936	SCV004192160	uncertain significance	Familial adenomatous polyposis 1	2023-08-31	criteria provided, single submitter	clinical testing