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.835-8A>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA16618069

418007 (ClinVar)

Gene: APC

Condition: familial adenomatous polyposis 1

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 66b03d61-ff6d-446a-a8be-70e06e12d958

Approved on: 2023-02-18

Published on: 2023-03-14

HGVS expressions

NM_000038.6:c.835-8A>G

NM_000038.6(APC):c.835-8A>G

NC_000005.10:g.112815487A>G

CM000667.2:g.112815487A>G

NC_000005.9:g.112151184A>G

CM000667.1:g.112151184A>G

NC_000005.8:g.112179083A>G

NG_008481.4:g.127967A>G

ENST00000257430.9:c.835-8A>G

ENST00000257430.8:c.835-8A>G

ENST00000507379.5:c.781-8A>G

ENST00000508376.6:c.835-8A>G

ENST00000508624.5:c.*157-8A>G

ENST00000512211.6:c.835-8A>G

NM_000038.5:c.835-8A>G

NM_001127510.2:c.835-8A>G

NM_001127511.2:c.781-8A>G

NM_001354895.1:c.835-8A>G

NM_001354896.1:c.835-8A>G

NM_001354897.1:c.865-8A>G

NM_001354898.1:c.760-8A>G

NM_001354899.1:c.751-8A>G

NM_001354900.1:c.658-8A>G

NM_001354901.1:c.658-8A>G

NM_001354902.1:c.865-8A>G

NM_001354903.1:c.835-8A>G

NM_001354904.1:c.760-8A>G

NM_001354905.1:c.658-8A>G

NM_001354906.1:c.-15-8A>G

NM_001127510.3:c.835-8A>G

NM_001127511.3:c.781-8A>G

NM_001354895.2:c.835-8A>G

NM_001354896.2:c.835-8A>G

NM_001354897.2:c.865-8A>G

NM_001354898.2:c.760-8A>G

NM_001354899.2:c.751-8A>G

NM_001354900.2:c.658-8A>G

NM_001354901.2:c.658-8A>G

NM_001354902.2:c.865-8A>G

NM_001354903.2:c.835-8A>G

NM_001354904.2:c.760-8A>G

NM_001354905.2:c.658-8A>G

NM_001354906.2:c.-15-8A>G

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PM2_Supporting PP3 PS3_Moderate PS4_Moderate

Evidence Links 0

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.835-8A>G variant in APC is an intronic variant 8 nucleotides upstream of the splice acceptor site for exon 9. The results from ≥2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 8 of APC (PP3). RNA data from carrier blood demonstrated aberrant splicing leading to a frameshift (PS3_Moderate; PMID 20649969; PMID 21779980). This alteration was identified in multiple individuals with a personal and/or family history consistent with familial adenomatous polyposis (PS4_Moderate; PMID 20649969, PMID 21779988; Ambry and GeneDx Internal Data). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3_Moderate; PS4_Moderate; PM2_Supporting, PP3 (VCEP specifications version 1; date of approval 12/12/2022).

PM2_Supporting

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

PP3

The results from ≥2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 8 of APC (PP3). In particular, SpliceAI gives a score of 0.78 for native acceptor site loss and 0.42 for a cryptic acceptor site gain 7 nucleotides upstream of the native site, predicting that the variant disrupts the native acceptor splice site of intron 8 of APC.

PS3_Moderate

RNA data from carrier blood demonstrated aberrant splicing leading to a frameshift (PS3_Moderate: PMID 20649969; PMID 21779980)

PS4_Moderate

This alteration was identified in multiple individuals with a personal and/or family history consistent with familial adenomatous polyposis (PMID 20649969; PMID 21779988; Ambry Internal Data; GeneDx Internal Data: 2.5 points = PS3_Moderate)

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.