Submissions for variant NM_000038.6(APC):c.5761G>A (p.Gly1921Ser)

dbSNP: rs1060503324

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV002523386	SCV003836608	uncertain significance	Familial adenomatous polyposis 1	2023-02-26	reviewed by expert panel	curation	The c.5761G>A variant in APC is a missense variant predicted to cause the substitution of glycine by serine at amino acid position 1921 (p.Gly1921Ser). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in more than 3 heterozygous individuals with no features of FAP, worth 3 healthy individual points (BS2_Supporting; Ambry Genetics internal data). A luciferase reporter plasmid transiently transfected into SW480 cells shows an inability to suppress beta-catenin-regulated transcription indicating that this variant impacts protein function (PS3_Supporting; PMID 18199528). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to conflicting evidence, this variant is classified as a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2_supporting, BP1, PM2_supporting, and PS3_supporting (VCEP specifications version 1; date of approval: 12/12/2022).
Invitae	RCV003651873	SCV000552644	uncertain significance	Familial adenomatous polyposis 1	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1921 of the APC protein (p.Gly1921Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multiple colorectal adenomas (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 411472). 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.
Ambry Genetics	RCV001024497	SCV001186522	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-18	criteria provided, single submitter	clinical testing	The p.G1921S variant (also known as c.5761G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 5761. The glycine at codon 1921 is replaced by serine, an amino acid with similar properties. This alteration was detected in one individual with 11-99 adenomatous colorectal polyps and was not detected in 969 matched healthy controls (Azzopardi D et al. Cancer Res., 2008 Jan;68:358-63). This amino acid position is not well 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.
Baylor Genetics	RCV002523386	SCV004197520	uncertain significance	Familial adenomatous polyposis 1	2023-10-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001024497	SCV004363482	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1921 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 been reported in an individual affected with colorectal adenomas (PMID: 18199528). 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.