NM_000038.6:c.70C>T
Variant summary
Our verdict is Uncertain significance. The variant received -3 ACMG points: 1P and 4B. BS2PS4_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.70C>T (p.Arg24Ter) in APC is a nonsense variant located 5’ of codon 49, thus PVS1 is not applicable based on the ACMG/AMP criteria specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.00002 (6/268,098 alleles), however, no value is given for the “filtering allele frequency” (FAF) (PM2_Supporting and BS1 not met). This variant has been observed in heterozygous state in 67 individuals, which are reported either with a very mild polyposis phenotype (only 3 carriers fulfilled 0.5 phenotype points each; PS4_Supporting) or without a colorectal cancer/polyposis associated phenotype (at least 10 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total; BS2) (PMID:28135145 and 18433509, internal data Ambry Genetics, GeneDX and Labcorp Genetics (formerly Invitae)). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criterion PS4_Supporting and BS2 applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA012843/MONDO:0021056/089
Frequency
Consequence
NM_000038.6 stop_gained
Scores
Clinical Significance
Conservation
Publications
- classic or attenuated familial adenomatous polyposisInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- desmoid tumorInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
- familial adenomatous polyposis 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
- gastric adenocarcinoma and proximal polyposis of the stomachInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- APC-related attenuated familial adenomatous polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Turcot syndrome with polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Cenani-Lenz syndactyly syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received -3 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| APC | NM_000038.6 | MANE Select | c.70C>T | p.Arg24* | stop_gained | Exon 2 of 16 | NP_000029.2 | ||
| APC | NM_001354906.2 | c.-966C>T | 5_prime_UTR_premature_start_codon_gain | Exon 2 of 17 | NP_001341835.1 | ||||
| APC | NM_001407470.1 | c.-966C>T | 5_prime_UTR_premature_start_codon_gain | Exon 2 of 17 | NP_001394399.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | TSL:5 MANE Select | c.70C>T | p.Arg24* | stop_gained | Exon 2 of 16 | ENSP00000257430.4 | ||
| APC | ENST00000508376.6 | TSL:1 | c.70C>T | p.Arg24* | stop_gained | Exon 3 of 17 | ENSP00000427089.2 | ||
| APC | ENST00000502371.3 | TSL:1 | n.70C>T | non_coding_transcript_exon | Exon 1 of 12 | ENSP00000484935.2 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.0000239 AC: 6AN: 251240 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461502Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727066 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:5Uncertain:2Other:1
The NM_000038.6(APC):c.70C>T (p.Arg24Ter) in APC is a nonsense variant located 5’ of codon 49, thus PVS1 is not applicable based on the ACMG/AMP criteria specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.00002 (6/268,098 alleles), however, no value is given for the “filtering allele frequency” (FAF) (PM2_Supporting and BS1 not met). This variant has been observed in heterozygous state in 67 individuals, which are reported either with a very mild polyposis phenotype (only 3 carriers fulfilled 0.5 phenotype points each; PS4_Supporting) or without a colorectal cancer/polyposis associated phenotype (at least 10 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total; BS2) (PMID: 28135145 and 18433509, internal data Ambry Genetics, GeneDX and Labcorp Genetics (formerly Invitae)). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criterion PS4_Supporting and BS2 applied (VCEP specifications version v2.1.0; date of approval 11/24/2023).
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
The APC c.70C>T (p.Arg24Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). Pathogenic variants in the 5’ end of the APC gene have been shown to be associated with an attenuated form of familial adenomatous polyposis since alternative translational initiation at codon 184 may result in a partially functional APC protein (PMID: 12034871, 16461775, 18433509). This variant has a maximum non-founder subpopulation frequency of 0.0016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/5-112090657-C-T). It has been reported in individuals with a personal and/or family history of attenuated familial adenomatous polyposis (PS4; PMID: 18433509, internal data), colorectal cancer (PMID: 28135145), and suspected Lynch syndrome (PMID: 25980754). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4.
This sequence change creates a premature translational stop signal (p.Arg24*) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). This variant is present in population databases (rs145945630, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and attenuated familial adenomatous polyposis (FAP) (PMID: 12034871, 16461775, 18433509, 25980754). ClinVar contains an entry for this variant (Variation ID: 184702). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
Variant classified as Pathogenic and reported on 06-11-2020 by Partners HealthCare Personalized Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Truncating variant in the 5' end of APC which has historically been considered to be associated with AFAP and lower penetrance. However, APC c.70C>T p.(Arg24*) is present in gnomAD at a frequency >0.001% and has also been observed in many healthy adults. According to the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0 this variant could possibly even reach a benign status (PVS1_not applicable, BS1, BS2). In the absence of formal case-control data, a classification as a variant of uncertain significance was applied.
not provided Pathogenic:2
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28590426, 26681312, 25980754, 30322717, 30720243, 31447099, 29625052, 26689913, 33442023, 32980694, 18433509)
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.R24* pathogenic mutation (also known as c.70C>T), located in coding exon 1 of the APC gene, results from a C to T substitution at nucleotide position 70. This changes the amino acid from an arginine to a stop codon within coding exon 1. This mutation has been reported in a Swedish individual diagnosed with attenuated FAP, a phenotype that supports the proposed thought of a milder form of polyposis caused by mutations in the 5' end of the gene (Kanter-Smoler G et al. BMC Med. 2008 Apr;6:10). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. However, alterations that result in premature termination in coding exon 1 are associated with an attenuated phenotype and may have reduced penetrance compared to classic familial adenomatous polyposis syndrome. Clinical correlation is advised.
This variant changes 1 nucleotide in exon 2 of the APC gene, creating a premature translation stop signal. Alterations that cause premature truncation in the amino (N-) terminus of the APC protein have been associated with an attenuated phenotype and may have reduced penetrance and/or expressivity in comparison to classic familial adenomatous polyposis syndrome (FAP; PMID: 9585611, 11257105). This nonsense variant has been observed in individuals affected with attenuated familial adenomatous polyposis (AFAP) as well as in individuals lacking clinical features of AFAP (PMID: 18433509, communications with external laboratories), which suggests that this variant may have reduced penetrance and/or expressivity compared to individuals with conventional AFAP (PMID: 34666312). This variant also has been reported in an individual affected with a Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 7/282632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic with reduced penetrance.
not specified Pathogenic:1
Familial multiple polyposis syndrome Pathogenic:1
The p.Arg24X variant in APC has been reported in 1 individual with attenuated familial adenomatous polyposis (AFAP) and 1 individual with suspected Lynch syndrome (Kanter-Smoler 2008, Yurgelun 2015) and has also been reported by other clinical laboratories in ClinVar (Variant ID 184702). It has been identified in 4/25788 Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 24, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the APC gene is an established disease mechanism in individuals with FAP. However, truncating variants in the 5' end of the APC gene, where this variant is located, have typically been associated with AFAP (Jasperson 2017). In summary, this variant meets criteria to be classified as pathogenic for FAP, likely in the attenuated form, in an autosomal dominant manner, based upon predicted impact to the protein, presence in affected individuals, and frequency in the general population. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PS4_supporting.
Neoplasm of stomach;C0699790:Carcinoma of colon;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1 Pathogenic:1
Carcinoma of colon Pathogenic:1
The APC p.Arg24X variant was identified in 2 of 2712 proband chromosomes (frequency: 0.0007) from individuals or families with attenuated familial adenomatous polyposis (AFAP) (Kanter-Smoler 2008, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs145945630) as "With Pathogenic allele", ClinVar (5x, pathogenic/likely pathogenic), Clinvitae (2x, pathogenic), and the Insight Colon Cancer Gene Variant Database (1x). The variant was not identified in Cosmic, MutDB, UMD-LSDB, or the Zhejiang Colon Cancer Database. This variant was identified in the Genome Aggregation Consortium (Feb 27, 2017) in 5 (0 homozygous) of 276948 chromosomes (freq. 0.00002) in the following populations: Finnish in 4 of 25788 chromosomes (freq. 0.0002) and European in 1 of 126482 chromosomes (freq. 0.000008). The p.Arg24X variant leads to a premature stop codon at position 24. This alteration would typically be predicted to result in a truncated or absent protein and loss of function. However, one study has demonstrated that for APC mutations closer to the 5’ terminus, an internal ribosome entry site is utilized to initiate translation at codon 184, resulting in a partially functional N-terminally truncated protein, which results in an attenuated phenotype (Heppner Goss 2002). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Attenuated familial adenomatous polyposis Pathogenic:1
Variant summary: APC c.70C>T (p.Arg24X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Some truncating mutations in the 5' end of the APC gene have been found to be associated with an attenuated phenotype of familial adenomatous polyposis coli (AFAP), as it was demonstrated that a downstream in-frame alternative start codon (codon 184) may generate a partially functional protein (see e.g. PMID: 12034871). However, to our knowledge, no experimental evidence demonstrating this scenario has been reported for the variant of interest. The variant allele was found at a frequency of 2.4e-05 in 251240 control chromosomes. c.70C>T has been reported in the literature in an individual affected with AFAP (Kanter-Smoler 2008) and in an other individual affected with Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18433509, 25980754). ClinVar contains an entry for this variant (Variation ID: 184702). Based on the evidence outlined above, the variant was classified as pathogenic.
Gastric cancer Pathogenic:1
Classic or attenuated familial adenomatous polyposis Pathogenic:1
This variant changes 1 nucleotide in exon 2 of the APC gene, creating a premature translation stop signal. Alterations that cause premature truncation in the amino (N-) terminus of the APC protein have been associated with an attenuated phenotype and may have reduced penetrance and/or expressivity in comparison to classic familial adenomatous polyposis syndrome (FAP; PMID: 9585611, 11257105). This nonsense variant has been observed in individuals affected with attenuated familial adenomatous polyposis (AFAP) as well as in individuals lacking clinical features of AFAP (PMID: 18433509, communications with external laboratories), which suggests that this variant may have reduced penetrance and/or expressivity compared to individuals with conventional AFAP (PMID: 34666312). This variant also has been reported in an individual affected with a Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 7/282632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic with reduced penetrance.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at