Submissions for variant NM_000038.6(APC):c.3755C>T (p.Ser1252Phe)

dbSNP: rs1554085281

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004568943	SCV000647472	uncertain significance	Familial adenomatous polyposis 1	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1252 of the APC protein (p.Ser1252Phe). This variant is not present in population databases (gnomAD no frequency). 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: 469939). 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 with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000580158	SCV000681630	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-19	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 1252 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has not been identified 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.
Ambry Genetics	RCV000580158	SCV001182624	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-27	criteria provided, single submitter	clinical testing	The p.S1252F variant (also known as c.3755C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3755. The serine at codon 1252 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001775865	SCV002013122	uncertain significance	not provided	2019-06-19	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
All of Us Research Program, National Institutes of Health	RCV003999388	SCV004837836	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 1252 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has not been identified 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.