Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000038.6(APC):c.5761G>A (p.Gly1921Ser)

411472 (ClinVar)

Gene: APC
Condition: familial adenomatous polyposis 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: af3168e2-cf37-48a0-8db8-814e49bf0554
Approved on: 2023-02-26
Published on: 2023-03-14

HGVS expressions

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

Uncertain Significance

Met criteria codes 4
PM2_Supporting BS2_Supporting BP1 PS3_Supporting

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
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).
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
BS2_Supporting
This variant has been observed in more than three heterozygous individuals with no features of familial adenomatous polyposis (Ambry internal data, BS2_supporting).
BP1
APC, in which the variant was identified, is defined by the ClinGen APC VCEP as a gene for which primarily truncating variants are known to cause disease (BP1).
PS3_Supporting
A luciferase reporter plasmid transiently transfected into SW480 cells showed an inability to suppress beta-catenin-regulated transcription indicating that this variant impacts protein function (PMID 18199528)(PS3_supporting).
TopFlash normalized to FopFlash luciferase reporter assay transfected into SW480 colorectal cancer cell line reflects an inability to inhibit TopFlash (Beta-catenin driven transcription) activity similar to LoF alterations. PubMed:18199528
Curation History
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