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
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000038.6(APC):c.1042C>T (p.Arg348Ter)

CA16021325

955439 (ClinVar)

Gene: APC (HGNC:324)
Condition: familial adenomatous polyposis 1 (MONDO:0021056)
Inheritance Mode: Autosomal dominant inheritance
UUID: 011221f1-ca1b-4750-9435-03f4f4380288
Approved on: 2025-05-16
Published on: 2025-05-16

HGVS expressions

NM_000038.6(APC):c.1042C>T (p.Arg348Ter)
NM_000038.6:c.1042C>T
NC_000005.10:g.112819074C>T
CM000667.2:g.112819074C>T
NC_000005.9:g.112154771C>T
CM000667.1:g.112154771C>T
NC_000005.8:g.112182670C>T
NG_008481.4:g.131554C>T
ENST00000502371.3:c.1042C>T
ENST00000504915.3:c.1042C>T
ENST00000505084.2:n.1098C>T
ENST00000505350.2:c.*1048C>T
ENST00000507379.6:c.988C>T
ENST00000509732.6:c.1042C>T
ENST00000512211.7:c.1042C>T
ENST00000257430.9:c.1042C>T
ENST00000257430.8:c.1042C>T
ENST00000507379.5:c.988C>T
ENST00000508376.6:c.1042C>T
ENST00000508624.5:c.*364C>T
ENST00000512211.6:c.1042C>T
NM_000038.5:c.1042C>T
NM_001127510.2:c.1042C>T
NM_001127511.2:c.988C>T
NM_001354895.1:c.1042C>T
NM_001354896.1:c.1042C>T
NM_001354897.1:c.1072C>T
NM_001354898.1:c.967C>T
NM_001354899.1:c.958C>T
NM_001354900.1:c.865C>T
NM_001354901.1:c.865C>T
NM_001354902.1:c.964-195C>T
NM_001354903.1:c.934-195C>T
NM_001354904.1:c.859-195C>T
NM_001354905.1:c.757-195C>T
NM_001354906.1:c.193C>T
NM_001127510.3:c.1042C>T
NM_001127511.3:c.988C>T
NM_001354895.2:c.1042C>T
NM_001354896.2:c.1042C>T
NM_001354897.2:c.1072C>T
NM_001354898.2:c.967C>T
NM_001354899.2:c.958C>T
NM_001354900.2:c.865C>T
NM_001354901.2:c.865C>T
NM_001354902.2:c.964-195C>T
NM_001354903.2:c.934-195C>T
NM_001354904.2:c.859-195C>T
NM_001354905.2:c.757-195C>T
NM_001354906.2:c.193C>T
More

Uncertain Significance

Met criteria codes 3
PS4_Supporting BS2_Supporting PM2_Supporting
Not Met criteria codes 1
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.1042C>T variant in APC is predicted to cause a premature stop codon (p.R348Ter) located between codon 49 and 2645 in biologically relevant exon 10 (coding exon 9) in a gene in which loss-of-function is an established disease mechanism. However, based on unpublished RNA analyses from Ambry Genetics, the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) does not consider this variant to be applicable to PVS1. The RNA analyses showed that this variant results in an in-frame aberrant transcript lacking part of exon 10 [r.934_1074del (p.V312_Q358del)]. In addition, an increased expression of a naturally occurring alternative transcript (r.934_1236del (p.V312_Q412del), known as “exon 9a”) was observed relative to controls. The predicted premature stop codon (p.R348Ter) was excluded from both the aberrant and naturally occurring transcripts and might provide a rescue mechanism for this nonsense alteration. The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000004 (1/251004 alleles), which is lower than the HCCP VCEP threshold 0.00001 for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). This variant has been reported in three families with a polyposis phenotype, resulting in a total phenotype score of 1.5 points (PS4_Supporting, [PMID: 11754114 and 12007223; CanVIG-UK]). On the other hand, this variant has been observed in heterozygous state in 7 healthy unrelated adult individuals worth ≥ 6 healthy individual points in total (BS2_Supporting; [Ambry Genetics, Invitae, UK Biobank, 100,000 Genomes Project]). Due to conflicting evidence, this variant is classified as a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PS4_Supporting, PM2_Supporting and BS2_Supporting applied (VCEP specifications version 2.0.3; date of approval 7/24/2023).
Met criteria codes
PS4_Supporting
This variant has been reported in three families with a polyposis phenotype, resulting in a total phenotype score of 1.5 points (PS4_Supporting, [PMID: 11754114 and 12007223; CanVIG-UK]).
BS2_Supporting
This variant has been observed in heterozygous state in 7 healthy unrelated adult individuals worth ≥ 6 healthy individual points in total (BS2_Supporting; [Ambry Genetics, Invitae, UK Biobank, 100,000 Genomes Project]).
PM2_Supporting
The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000004 (1/251004 alleles), which is lower than the HCCP VCEP threshold 0.00001 for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting).
Not Met criteria codes
PVS1
The NM_000038.6(APC):c.1042C>T variant in APC is predicted to cause a premature stop codon (p.R348Ter) located between codon 49 and 2645 in biologically relevant exon 10 (coding exon 9) in a gene in which loss-of-function is an established disease mechanism. However, based on unpublished RNA analyses from Ambry Genetics, the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) does not consider this variant to be applicable to PVS1. The RNA analyses showed that this variant results in an in-frame aberrant transcript lacking part of exon 10 [r.934_1074del (p.V312_Q358del)]. In addition, an increased expression of a naturally occurring alternative transcript (r.934_1236del (p.V312_Q412del), known as “exon 9a”) was observed relative to controls. The predicted premature stop codon (p.R348Ter) was excluded from both the aberrant and naturally occurring transcripts and might provide a rescue mechanism for this nonsense alteration.
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
ClinGen Terms of Use.
¤ Powered by BCM's Genboree.