Submissions for variant NM_000038.6(APC):c.5888T>C (p.Phe1963Ser)

gnomAD frequency: 0.00001  dbSNP: rs1411885238

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001183434	SCV001349154	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with serine at codon 1963 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 not been reported in individuals affected with hereditary cancer 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004564611	SCV001517082	uncertain significance	Familial adenomatous polyposis 1	2021-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine with serine at codon 1963 of the APC protein (p.Phe1963Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC 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: 923047). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV001183434	SCV002649494	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-27	criteria provided, single submitter	clinical testing	The p.F1963S variant (also known as c.5888T>C), located in coding exon 15 of the APC gene, results from a T to C substitution at nucleotide position 5888. The phenylalanine at codon 1963 is replaced by serine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV004008383	SCV004838115	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with serine at codon 1963 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 not been reported in individuals affected with hereditary cancer 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.