Submissions for variant NM_000038.6(APC):c.70C>T (p.Arg24Ter)

gnomAD frequency: 0.00003  dbSNP: rs145945630

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164002	SCV000214605	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227124	SCV000282812	pathogenic	Familial adenomatous polyposis 1	2024-12-11	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000227124	SCV000488376	likely pathogenic	Familial adenomatous polyposis 1	2016-03-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000482864	SCV000568259	pathogenic	not provided	2022-09-20	criteria provided, single submitter	clinical testing	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)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508297	SCV000602530	pathogenic	not specified	2017-01-12	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844605	SCV000731596	pathogenic	Familial multiple polyposis syndrome	2020-03-03	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000763534	SCV000894347	pathogenic	Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164002	SCV000905870	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-08	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689634	SCV000918469	pathogenic	Attenuated familial adenomatous polyposis	2024-05-13	criteria provided, single submitter	clinical testing	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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000482864	SCV001449970	pathogenic	not provided	2019-12-06	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000227124	SCV001761635	pathogenic	Familial adenomatous polyposis 1	2021-07-22	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV000227124	SCV004017725	pathogenic	Familial adenomatous polyposis 1	2023-02-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000227124	SCV004200309	pathogenic	Familial adenomatous polyposis 1	2023-09-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995307	SCV004841690	likely pathogenic	Classic or attenuated familial adenomatous polyposis	2024-07-10	criteria provided, single submitter	clinical testing	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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000227124	SCV005199548	uncertain significance	Familial adenomatous polyposis 1	2024-10-04	criteria provided, single submitter	clinical testing	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353710	SCV000591013	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	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.
Laboratory for Genotyping Development, RIKEN	RCV003162685	SCV002758044	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research