ClinVar Miner

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

dbSNP: rs1060503324
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Total submissions: 6
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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 RCV002523386 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, 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.
Baylor Genetics RCV002523386 SCV004197520 uncertain significance Familial adenomatous polyposis 1 2024-03-09 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.
All of Us Research Program, National Institutes of Health RCV004001955 SCV004838104 uncertain significance Classic or attenuated familial adenomatous polyposis 2023-11-30 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.

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