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]

Variant: NM_000038.6(APC):c.1409-5A>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA16611764

411406 (ClinVar)

Gene: APC

Condition: familial adenomatous polyposis 1

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3c5a822e-2957-482b-a043-c16296b35905

Approved on: 2025-05-16

Published on: 2025-05-16

HGVS expressions

NM_000038.6:c.1409-5A>G

NM_000038.6(APC):c.1409-5A>G

NC_000005.10:g.112827103A>G

CM000667.2:g.112827103A>G

NC_000005.9:g.112162800A>G

CM000667.1:g.112162800A>G

NC_000005.8:g.112190699A>G

NG_008481.4:g.139583A>G

ENST00000502371.3:c.1408+5112A>G

ENST00000504915.3:c.1463-5A>G

ENST00000505084.2:n.1465-5A>G

ENST00000505350.2:c.*1415-5A>G

ENST00000507379.6:c.1355-5A>G

ENST00000509732.6:c.1409-5A>G

ENST00000512211.7:c.1409-5A>G

ENST00000257430.9:c.1409-5A>G

ENST00000257430.8:c.1409-5A>G

ENST00000502371.2:c.96+5112A>G

ENST00000504915.2:c.98-5A>G

ENST00000507379.5:c.1355-5A>G

ENST00000508376.6:c.1409-5A>G

ENST00000508624.5:c.*731-5A>G

ENST00000512211.6:c.1409-5A>G

NM_000038.5:c.1409-5A>G

NM_001127510.2:c.1409-5A>G

NM_001127511.2:c.1355-5A>G

NM_001354895.1:c.1409-5A>G

NM_001354896.1:c.1463-5A>G

NM_001354897.1:c.1439-5A>G

NM_001354898.1:c.1334-5A>G

NM_001354899.1:c.1325-5A>G

NM_001354900.1:c.1286-5A>G

NM_001354901.1:c.1232-5A>G

NM_001354902.1:c.1136-5A>G

NM_001354903.1:c.1106-5A>G

NM_001354904.1:c.1031-5A>G

NM_001354905.1:c.929-5A>G

NM_001354906.1:c.560-5A>G

NM_001127510.3:c.1409-5A>G

NM_001127511.3:c.1355-5A>G

NM_001354895.2:c.1409-5A>G

NM_001354896.2:c.1463-5A>G

NM_001354897.2:c.1439-5A>G

NM_001354898.2:c.1334-5A>G

NM_001354899.2:c.1325-5A>G

NM_001354900.2:c.1286-5A>G

NM_001354901.2:c.1232-5A>G

NM_001354902.2:c.1136-5A>G

NM_001354903.2:c.1106-5A>G

NM_001354904.2:c.1031-5A>G

NM_001354905.2:c.929-5A>G

NM_001354906.2:c.560-5A>G

Likely Pathogenic

PS3_Moderate PP3 PS4_Moderate PM2_Supporting

BS2

Evidence Links 1

Expert Panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Criteria Specification Information

Criteria Specification: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

The NM_000038.6(APC):c.1409-5A>G variant in APC is an intronic variant which is located at the 5th nucleotide upstream of exon 12. This variant has been reported in 5 probands meeting phenotypic criteria resulting in a total phenotype score of 3.0 points (PS4_Moderate, Invitae internal data, PMID: 24599579, 20685668, 20223039, 15459959, 11247896). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from ≥ 2 in silico splicing predictors (SpliceAI and VarSeak) indicate that this variant may affect splicing by disrupting the acceptor site of intron 11 of APC by creating a strong alternate acceptor site 5 nucleotides upstream (PP3). Mini-gene assay demonstrated that the variant impacts splicing by skipping of exon 12 resulting in a frameshift and premature termination (PS3_Moderate [PMID: 20685668, 24599579]). The mini-gene assay demonstrated also the retention of the last 4 nucleotides of the upstream intron as a minor effect, corresponding to the creation of an alternate acceptor site 5 nucleotides upstream and also resulting in a frameshift and premature termination (internal data Normandy University, Rouen, France). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: criteria PS3_Moderate, PS4_Moderate, PM2_Supporting and PP3 applied (VCEP specifications version 2.0.3; date of approval: 7/24/2023).

PS3_Moderate

Mini-gene assay demonstrated that the variant impacts splicing by skipping of exon 12 resulting in a frameshift and premature termination (PS3_Moderate [PMID: 20685668, 24599579]). The mini-gene assay demonstrated also the retention of the last 4 nucleotides of the upstream intron as a minor effect, corresponding to the creation of an alternate acceptor site 5 nucleotides upstream and also resulting in a frameshift and premature termination (internal data Normandy University, Rouen, France).

Description of the observed effect from ex vivo splicing analysis: p.Gly470GlyfsX20 (Exon 11 deletion). Likely redundant with Grandval and not an independent assay. This result differs from the predicted event which is a small insertion: r.1408_1409insTTAG (p.(Gly470Valfs*16)) PubMed:20685668

PP3

The results from ≥ 2 in silico splicing predictors (SpliceAI and VarSeak) indicate that this variant may affect splicing by disrupting the acceptor site of intron 11 of APC by creating a strong alternate acceptor site 5 nucleotides upstream (PP3).

PS4_Moderate

This variant has been reported in 5 probands meeting phenotypic criteria resulting in a total phenotype score of 3.0 points (PS4_Moderate, Invitae internal data, PMID: 24599579, 20685668, 20223039, 15459959, 11247896).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

BS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.