rs137854575
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.2805C>A(p.Tyr935Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y935Y) has been classified as Benign.
Frequency
Genomes: not found (cov: 32)
Consequence
APC
NM_000038.6 stop_gained
NM_000038.6 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 1.44
Genes affected
APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 235 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-112838399-C-A is Pathogenic according to our data. Variant chr5-112838399-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838399-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| APC | NM_000038.6 | c.2805C>A | p.Tyr935Ter | stop_gained | 16/16 | ENST00000257430.9 | NP_000029.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | c.2805C>A | p.Tyr935Ter | stop_gained | 16/16 | 5 | NM_000038.6 | ENSP00000257430 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:17Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6Uncertain:1
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
| Pathogenic, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2023 | 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; Observed in multiple unrelated patients with Familial Adenomatous Polyposis (FAP) referred for genetic testing at GeneDx and in published literature (Fodde et al., 1992; Won et al., 1999; Aceto et al., 2005; Kim et al., 2005; Agatea et al., 2015; Simbolo et al., 2015; Khan et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26917275, 16134147, 1324223, 26300997, 28533537, 27978560, 29753700, 18199528, 16292097, 35189564, 35142982, 26792031, 10083733, 16088911) - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jan 14, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 11, 2023 | The APC c.2805C>A (p.Tyr935*) variant causes the premature termination of APC protein synthesis. This variant has been reported in the published literature in several individuals and families affected with FAP (PMID: 35142982 (2022), 26300997 (2015), 23970361 (2013), 20924072 (2011), 12173026 (2002)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
Familial adenomatous polyposis 1 Pathogenic:6
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1992 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 05, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 16, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2024 | This sequence change creates a premature translational stop signal (p.Tyr935*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1909 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with FAP and thyroid cancer and familial adenomatous polyposis (FAP) (PMID: 1324223, 1944466, 8381579, 8990002, 10083733, 10094547, 10713886, 11748858, 11933206, 12173026, 15024739, 15108288, 16088911, 16317745, 17411426, 19793053, 20685668, 20924072, 26300997). ClinVar contains an entry for this variant (Variation ID: 810). This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 29, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 22, 2024 | The p.Y935* pathogenic mutation (also known as c.2805C>A), located in coding exon 15 of the APC gene, results from a C to A substitution at nucleotide position 2805. This changes the amino acid from a tyrosine to a stop codon within coding exon 15. This pathogenic mutation has been reported in numerous families with Familial Adenomatous Polyposis (FAP) (van der Luijt RB et al. Hum. Mutat.1997;9:7-16; Friedl W et al. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Kim DW et al. Hum. Mutat. 2005 Sep;26:281; Kanter-Smoler G et al. BMC Med. 2008 Apr;6:10; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 20, 2020 | This variant changes 1 nucleotide in exon 16 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple families and individuals affected with colorectal polyposis and cancer (PMID: 1324223, 8381579, 10083733, 10094547, 10713886, 11748858, 12173026, 15024739, 16088911, 17411426, 19444466, 20685668, 20924072). This variant also has been reported in individuals affected with osteoma (PMID: 19444466) and hepatoblastoma (PMID: 16317745). This variant has not been identified 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 Pathogenic. - |
Familial multiple polyposis syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 27, 2014 | The Tyr935X variant in APC has been reported in >20 individuals with FAP, segreg ated with disease in at least 12 affected family members (see references), and w as absent from large population studies (rs137854575). This nonsense variant le ads to a premature termination codon at position 935, 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. In summary, this v ariant meets our criteria to be classified as pathogenic (http://pcpgm.partners. org/LMM) based upon segregation studies and absence from controls. - |
Neoplasm of stomach;C0699790:Carcinoma of colon;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Colorectal cancer, susceptibility to Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D
Vest4
0.95, 0.94
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at