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.4399C>T (p.Pro1467Ser)

CA038968

411419 (ClinVar)

Gene: APC
Condition: familial adenomatous polyposis 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f031e81a-43da-4a40-98d9-f4b196924ffd
Approved on: 2023-02-26
Published on: 2023-03-14

HGVS expressions

NM_000038.6:c.4399C>T
NM_000038.6(APC):c.4399C>T (p.Pro1467Ser)
NC_000005.10:g.112839993C>T
CM000667.2:g.112839993C>T
NC_000005.9:g.112175690C>T
CM000667.1:g.112175690C>T
NC_000005.8:g.112203589C>T
NG_008481.4:g.152473C>T
ENST00000257430.9:c.4399C>T
ENST00000257430.8:c.4399C>T
ENST00000508376.6:c.4399C>T
ENST00000508624.5:c.*3721C>T
ENST00000520401.1:n.230+11021C>T
NM_000038.5:c.4399C>T
NM_001127510.2:c.4399C>T
NM_001127511.2:c.4345C>T
NM_001354895.1:c.4399C>T
NM_001354896.1:c.4453C>T
NM_001354897.1:c.4429C>T
NM_001354898.1:c.4324C>T
NM_001354899.1:c.4315C>T
NM_001354900.1:c.4276C>T
NM_001354901.1:c.4222C>T
NM_001354902.1:c.4126C>T
NM_001354903.1:c.4096C>T
NM_001354904.1:c.4021C>T
NM_001354905.1:c.3919C>T
NM_001354906.1:c.3550C>T
NM_001127510.3:c.4399C>T
NM_001127511.3:c.4345C>T
NM_001354895.2:c.4399C>T
NM_001354896.2:c.4453C>T
NM_001354897.2:c.4429C>T
NM_001354898.2:c.4324C>T
NM_001354899.2:c.4315C>T
NM_001354900.2:c.4276C>T
NM_001354901.2:c.4222C>T
NM_001354902.2:c.4126C>T
NM_001354903.2:c.4096C>T
NM_001354904.2:c.4021C>T
NM_001354905.2:c.3919C>T
NM_001354906.2:c.3550C>T
More

Benign

Met criteria codes 5
BS1 BS2 BP5 BP1 BS3_Supporting
Not Met criteria codes 3
PP3 BP4 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.4399C>T variant in APC is a missense variant predicted to cause the substitution of Proline by Serine at amino acid position 1467 (p.Pro1467Ser). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in a heterozygous state in 75 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics, Invitae and GeneDX internal data). In addition, it has also been observed in 1 patient with an alternate molecular basis for disease – a pathogenic MSH6 germline variant (BP5; Melbourne Internal data). Functional study of β-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as the wild type (BS3_Supporting; PMID: 18199528). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0048% in European (non-Finnish) population, which is higher than the HCCP VCEP threshold (≥ 0.001%) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS1, BS2, BS3_Supporting, BP1 and BP5 (VCEP Specification version 1, date of approval: 12/12/2022).
Met criteria codes
BS1
The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0048% in European (non-Finnnish) population, which is higher than the ClinGenInSiGHT Hereditary Colorectal Cancer/Polyposis threshold (≥ 0.001%) for BS1, and therefore meets this criterion (BS1).
BS2
This variant has been observed in heterozygous state in 75 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics, Invitae and GeneDX internal data).
BP5
This variant has been observed in 1 patient with an alternate molecular basis for disease – this patient had a pathogenic MSH6 variant. (BP5; Melbourne Internal data).
BP1
APC, in which the variant was identified, is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP as a gene for which primarily truncating variants are known to cause disease (BP1).
BS3_Supporting
Functional study of β-catenin-regulated transcription assays indicated that this alteration suppressed CRT as effectively as wild type (BS3_Supporting; PMID: 18199528).
Not Met criteria codes
PP3
Multiple lines of computational evidence suggest no splicing impact (SpliceAI and varSEAK).
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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