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]
  • Gene label mismatch: APC vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • Despite there being a valid 'cspec' property in the messages there's a discrepancy in message contents and CSPEC data: * Message Gene: APC CSPEC Genes: [ 'APC' ] * Message MONDOs: MONDO:0021055 CSPEC MONDO: [ 'MONDO:0021056' ]
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000038.6(APC):c.220+2T>A

CA007244

141515 (ClinVar)

Gene: APC
Condition: classic familial adenomatous polyposis
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 82e95160-be25-4a02-ae6e-b7ac8f7ebab3
Approved on: 2025-05-16
Published on: 2025-05-16

HGVS expressions

NM_000038.6:c.220+2T>A
NM_000038.6(APC):c.220+2T>A
NC_000005.10:g.112766412T>A
CM000667.2:g.112766412T>A
NC_000005.9:g.112102109T>A
CM000667.1:g.112102109T>A
NC_000005.8:g.112130008T>A
NG_008481.4:g.78892T>A
ENST00000502371.3:c.220+2T>A
ENST00000504915.3:c.220+2T>A
ENST00000505084.2:n.276+2T>A
ENST00000505350.2:c.*226+2T>A
ENST00000507379.6:c.250+2T>A
ENST00000509732.6:c.220+2T>A
ENST00000512211.7:c.220+2T>A
ENST00000257430.9:c.220+2T>A
ENST00000257430.8:c.220+2T>A
ENST00000507379.5:c.250+2T>A
ENST00000508376.6:c.220+2T>A
ENST00000508624.5:c.220+2T>A
ENST00000509732.5:c.220+2T>A
ENST00000512211.6:c.220+2T>A
NM_000038.5:c.220+2T>A
NM_001127510.2:c.220+2T>A
NM_001127511.2:c.250+2T>A
NM_001354895.1:c.220+2T>A
NM_001354896.1:c.220+2T>A
NM_001354897.1:c.250+2T>A
NM_001354898.1:c.145+2T>A
NM_001354899.1:c.220+2T>A
NM_001354900.1:c.43+2T>A
NM_001354901.1:c.43+2T>A
NM_001354902.1:c.250+2T>A
NM_001354903.1:c.220+2T>A
NM_001354904.1:c.145+2T>A
NM_001354905.1:c.43+2T>A
NM_001354906.1:c.-816+2T>A
NM_001127510.3:c.220+2T>A
NM_001127511.3:c.250+2T>A
NM_001354895.2:c.220+2T>A
NM_001354896.2:c.220+2T>A
NM_001354897.2:c.250+2T>A
NM_001354898.2:c.145+2T>A
NM_001354899.2:c.220+2T>A
NM_001354900.2:c.43+2T>A
NM_001354901.2:c.43+2T>A
NM_001354902.2:c.250+2T>A
NM_001354903.2:c.220+2T>A
NM_001354904.2:c.145+2T>A
NM_001354905.2:c.43+2T>A
NM_001354906.2:c.-816+2T>A
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Pathogenic

Met criteria codes 3
PS4 PM2_Supporting PVS1

Evidence Links 0

Expert Panel

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.220+2T>A variant in APC occurs within the canonical splice donor site (+2) of intron 3. RT-PCR and CaptureSeq of patient cDNA demonstrated that the variant impacts splicing by creating a substantial but incomplete aberrant splice defect that is predicted to cause a premature stop codon (r.220+1_220+15ins15 (p.K73_E74insGRF*)) (PVS1, [internal data from Ambry Genetics, Invitae, Copenhagen University Hospital]). This variant has been reported in 25 probands/families meeting phenotypic criteria, resulting in a total phenotype score of 13.5 points (PS4, [Ambry Genetics, Invitae]). Moreover, the variant has been observed in heterozygous state in 20 additional individuals with a “Colorectal cancer/polyposis associated phenotype,” however, the available phenotype information is not sufficient to assign phenotype points (Invitae). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PVS1, PS4, PM2_Supporting (VCEP specifications v2.1.0; date of approval 11/24/2023).
Met criteria codes
PS4
This variant has been reported in 25 probands/families meeting phenotypic criteria, resulting in a total phenotype score of 13.5 points (PS4, [Ambry Genetics, Invitae]). Moreover, the variant has been observed in heterozygous state in 20 additional individuals with a “Colorectal cancer/polyposis associated phenotype,” however, the available phenotype information is not sufficient to assign phenotype points (Invitae).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PVS1
The NM_000038.6(APC):c.220+2T>A variant in APC occurs within the canonical splice donor site (+2) of intron 3. RT-PCR and CaptureSeq of patient cDNA demonstrated that the variant impacts splicing by creating a substantial but incomplete aberrant splice defect that is predicted to cause a premature stop codon (r.220+1_220+15ins15 (p.K73_E74insGRF*)) (PVS1, [internal data from Ambry Genetics, Invitae, Copenhagen University Hospital]).
Curation History
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