Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000038.6(APC):c.4732T>G (p.Cys1578Gly)

CA009712

140839 (ClinVar)

Gene: APC

Condition: familial adenomatous polyposis 1

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c2613d9b-a942-4a42-bbc5-92125874c88b

HGVS expressions

NM_000038.6:c.4732T>G

NM_000038.6(APC):c.4732T>G (p.Cys1578Gly)

NC_000005.10:g.112840326T>G

CM000667.2:g.112840326T>G

NC_000005.9:g.112176023T>G

CM000667.1:g.112176023T>G

NC_000005.8:g.112203922T>G

NG_008481.4:g.152806T>G

ENST00000257430.9:c.4732T>G

ENST00000257430.8:c.4732T>G

ENST00000508376.6:c.4732T>G

ENST00000508624.5:c.*4054T>G

ENST00000520401.1:n.230+11354T>G

NM_000038.5:c.4732T>G

NM_001127510.2:c.4732T>G

NM_001127511.2:c.4678T>G

NM_001354895.1:c.4732T>G

NM_001354896.1:c.4786T>G

NM_001354897.1:c.4762T>G

NM_001354898.1:c.4657T>G

NM_001354899.1:c.4648T>G

NM_001354900.1:c.4609T>G

NM_001354901.1:c.4555T>G

NM_001354902.1:c.4459T>G

NM_001354903.1:c.4429T>G

NM_001354904.1:c.4354T>G

NM_001354905.1:c.4252T>G

NM_001354906.1:c.3883T>G

NM_001127510.3:c.4732T>G

NM_001127511.3:c.4678T>G

NM_001354895.2:c.4732T>G

NM_001354896.2:c.4786T>G

NM_001354897.2:c.4762T>G

NM_001354898.2:c.4657T>G

NM_001354899.2:c.4648T>G

NM_001354900.2:c.4609T>G

NM_001354901.2:c.4555T>G

NM_001354902.2:c.4459T>G

NM_001354903.2:c.4429T>G

NM_001354904.2:c.4354T>G

NM_001354905.2:c.4252T>G

NM_001354906.2:c.3883T>G

Uncertain Significance

BS3_Supporting BP1 PS4

PM2

Evidence Links 1

Expert Panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

The c.4732T>G variant in APC is a missense variant predicted to cause the substitution of cysteine by glycine at amino acid position 1578 (p.Cys1578Gly). This variant has been reported in 21 families with FAP worth 9 phenotype points (PS4, Ambry, GeneDX and Invitae internal data). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.0009780% in the non-Finnish European population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel’s (HCCP VCEP) threshold ≤ 0.0008% for PM2_Supporting (PM2_Supporting not met). A luciferase reporter plasmid transiently transfected into SW480 cells is able to suppress beta-catenin-regulated transcription indicating that this variant does not impact protein function (BS3_Supporting; PMID 18199528). APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). 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: PS4, BS3_Supporting, BP1 (VCEP specifications version 1; date of approval: 12/12/2022).

BS3_Supporting

A luciferase reporter plasmid transiently transfected into SW480 cells was able to suppress beta-catenin-regulated transcription indicating that this variant does not impact protein function (PMID 18199528)(BS3_supporting).

BP1

APC, in which the variant was identified, is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP as a gene for which primarily truncating variants are known to cause disease (BP1).

PS4

This variant has been reported in many families with familial adenomatous polyposis (Ambry internal data; GeneDx internal data; Invitae internal data (9 points; PS4).

PM2

The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.000978% in the non-Finnish European population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold ≤ 0.0008% for PM2_Supporting.

Approved on: 2023-02-26

Published on: 2023-03-14

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