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.835-8A>G

CA16618069

418007 (ClinVar)

Gene: APC

Condition: familial adenomatous polyposis 1

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

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"

PS4_Moderate PP3 PM2_Supporting PS3_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).

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)

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.

PM2_Supporting

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

PS3_Moderate

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

Approved on: 2023-02-18

Published on: 2023-03-14

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