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.645+1G>A

CA279701

218000 (ClinVar)

Gene: APC
Condition: familial adenomatous polyposis 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: aa0fcded-1b23-4052-9aff-49c0d734f829
Approved on: 2023-02-18
Published on: 2023-03-14

HGVS expressions

NM_000038.6:c.645+1G>A
NM_000038.6(APC):c.645+1G>A
NC_000005.10:g.112780904G>A
CM000667.2:g.112780904G>A
NC_000005.9:g.112116601G>A
CM000667.1:g.112116601G>A
NC_000005.8:g.112144500G>A
NG_008481.4:g.93384G>A
ENST00000257430.9:c.645+1G>A
ENST00000257430.8:c.645+1G>A
ENST00000507379.5:c.675+1G>A
ENST00000508376.6:c.645+1G>A
ENST00000508624.5:c.645+1G>A
ENST00000512211.6:c.645+1G>A
NM_000038.5:c.645+1G>A
NM_001127510.2:c.645+1G>A
NM_001127511.2:c.675+1G>A
NM_001354895.1:c.645+1G>A
NM_001354896.1:c.645+1G>A
NM_001354897.1:c.675+1G>A
NM_001354898.1:c.570+1G>A
NM_001354899.1:c.645+1G>A
NM_001354900.1:c.468+1G>A
NM_001354901.1:c.468+1G>A
NM_001354902.1:c.675+1G>A
NM_001354903.1:c.645+1G>A
NM_001354904.1:c.570+1G>A
NM_001354905.1:c.468+1G>A
NM_001354906.1:c.-391+1G>A
NM_001127510.3:c.645+1G>A
NM_001127511.3:c.675+1G>A
NM_001354895.2:c.645+1G>A
NM_001354896.2:c.645+1G>A
NM_001354897.2:c.675+1G>A
NM_001354898.2:c.570+1G>A
NM_001354899.2:c.645+1G>A
NM_001354900.2:c.468+1G>A
NM_001354901.2:c.468+1G>A
NM_001354902.2:c.675+1G>A
NM_001354903.2:c.645+1G>A
NM_001354904.2:c.570+1G>A
NM_001354905.2:c.468+1G>A
NM_001354906.2:c.-391+1G>A
More

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 3
PVS1_Moderate PM2_Supporting PS4
Not Met criteria codes 1
PS3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
The c.645+1G>A variant in APC occurs within the canonical splice donor site +1 of intron 6. It is predicted to result in an inframe skipping of exon 6 (PVS1_Moderate). The results from ≥2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) indicate that this variant may affect splicing by disrupting the donor splice site of intron 6 (PP3 supplanted by PVS1_Moderate). RT-PCR of patient blood demonstrated that the variant impacts splicing by removing exon 6 from the transcript, resulting in an NMD-escaping in-frame event with uncertain impact (PMID: 22987206, PS3 supplanted by PVS1_Moderate). This variant has been reported in 9 families with FAP with a total phenotype score of 6 points (PS4; Ambry, Invitae, GeneDX, Barcelona, Edinburgh and Leiden internal data; PMID 22987206; PMID 17411426; PMID 20685668; PMID 8381580). 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: PVS1_Moderate, PS4, and PM2_Supporting; (VCEP specifications version 1; date of approval: 12/12/2022).
Met criteria codes
PVS1_Moderate
The c.645+1G>A variant in APC occurs within the canonical splice donor site +1 of intron 6. It is predicted to result in an inframe exon skipping in a gene in which loss-of-function is an established disease mechanism (PVS1_Moderate).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PS4
This variant has been reported in 9 families with familial adenomatous polyposis, with a total phenotype score of 6 points (PS4; Ambry internal data; PMID 22987206; PMID 17411426; PMID 20685668; PMID 8381580).
Not Met criteria codes
PS3
RTPCR of patient blood demonstrated that the variant impacts splicing by removing exon 5 from the transcript, resulting in an NMD-escaping in-frame event with uncertain impact (PS3_variable not met; PMID 22987206).
Curation History
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