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.1240C>T (p.Arg414Cys)

CA004103

797 (ClinVar)

Gene: APC
Condition: familial adenomatous polyposis 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 164600c2-3e6f-449d-b8ba-1c2ec0a82479

HGVS expressions

NM_000038.6:c.1240C>T
NM_000038.6(APC):c.1240C>T (p.Arg414Cys)
NC_000005.10:g.112819272C>T
CM000667.2:g.112819272C>T
NC_000005.9:g.112154969C>T
CM000667.1:g.112154969C>T
NC_000005.8:g.112182868C>T
NG_008481.4:g.131752C>T
ENST00000257430.9:c.1240C>T
ENST00000257430.8:c.1240C>T
ENST00000507379.5:c.1186C>T
ENST00000508376.6:c.1240C>T
ENST00000508624.5:c.*562C>T
ENST00000512211.6:c.1240C>T
NM_000038.5:c.1240C>T
NM_001127510.2:c.1240C>T
NM_001127511.2:c.1186C>T
NM_001354895.1:c.1240C>T
NM_001354896.1:c.1240C>T
NM_001354897.1:c.1270C>T
NM_001354898.1:c.1165C>T
NM_001354899.1:c.1156C>T
NM_001354900.1:c.1063C>T
NM_001354901.1:c.1063C>T
NM_001354902.1:c.967C>T
NM_001354903.1:c.937C>T
NM_001354904.1:c.862C>T
NM_001354905.1:c.760C>T
NM_001354906.1:c.391C>T
NM_001127510.3:c.1240C>T
NM_001127511.3:c.1186C>T
NM_001354895.2:c.1240C>T
NM_001354896.2:c.1240C>T
NM_001354897.2:c.1270C>T
NM_001354898.2:c.1165C>T
NM_001354899.2:c.1156C>T
NM_001354900.2:c.1063C>T
NM_001354901.2:c.1063C>T
NM_001354902.2:c.967C>T
NM_001354903.2:c.937C>T
NM_001354904.2:c.862C>T
NM_001354905.2:c.760C>T
NM_001354906.2:c.391C>T

Benign

Met criteria codes 4
BA1 BP2 BP1 BS2
Not Met criteria codes 6
BP5 BP4 BS3 PP3 PS4 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.1240C>T variant in APC is a missense variant predicted to cause the substitution of arginine by cysteine at amino acid 414 (p.Arg414Cys). This variant has been observed in heterozygous state in ≥ 1000 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Invitae, Ambry, and GeneDX internal data). It has been observed in trans with a variant classified as Pathogenic by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) in an individual with FAP (BP2). The highest allele frequency of this variant is 0.001835 in European (Finnish) population, which is higher than the HCCP VCEP threshold (≥ 0.001) for BA1. Finally, APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). 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: BA1, BS2, BP1 and BP2 (VCEP specifications version 1; date of approval: 12/12/2022).
Met criteria codes
BA1
The highest population minor allele frequency of the variant c.1240C>T in gnomAD v2.1.1 (non-cancer) is 0.001835 (46/25066 alleles) in European (Finnish) population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis threshold threshold (≥ 0.001) for BA1, and therefore meets this criterion (BA1).
BP2
This variant has been observed in trans with a variant which is classified as pathogenic by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP in an individual with FAP (BP2).
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).
BS2
This variant has been observed in ≥ 500 individuals with no features or family history of FAP, a condition with full penetrance at an early age, and therefore meeting ≥ 10 healthy individual points (Invitae, Ambry, and GeneDX internal data).
Not Met criteria codes
BP5
This variant has been observed in co-occurrence with MSH2 and BARD1 respectively in 2 patients with unknown phenotype (BP5 not met; GeneDX internal data).
BP4
The results from ≥2 in silico splicing predictors SpliceAI and varSEAK support that this variant does not affect splicing (BP4 not applicable).
BS3
Dual luciferase assay in yeast cells showed retention of β-catenin regulated transcription activity comparable to wild-type indicating that this variant does not impact protein function. However, this rule is only applicable for variants within the β-catenin binding domain, which refers to codons 959-2129 of APC. Therefore, this variant does not meet BS3_Supporting as per the HCCP VCEP (BS3_Supporting not met; PMID14633595).
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
p.Val313_Gln412del (Exon 9 partial deletion) observed in ex vivo transcriptional assay, although no information was provided re level of expression of abnormal transcript or whether it was a controlled experiment.
Approved on: 2023-02-18
Published on: 2023-03-14
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