ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.147_150del (p.Lys49fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.147_150del (p.Lys49fs)
Variation ID: 141368 Accession: VCV000141368.37
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 5q22.2 5: 112766335-112766338 (GRCh38) [ NCBI UCSC ] 5: 112102032-112102035 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 21, 2017 Apr 20, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000038.6:c.147_150del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Lys49fs frameshift NM_000038.5:c.147_150del NM_001127510.3:c.147_150del NP_001120982.1:p.Lys49fs frameshift NM_001127511.3:c.177_180del NP_001120983.2:p.Lys59fs frameshift NM_001354895.2:c.147_150del NP_001341824.1:p.Lys49fs frameshift NM_001354896.2:c.147_150del NP_001341825.1:p.Lys49fs frameshift NM_001354897.2:c.177_180del NP_001341826.1:p.Lys59fs frameshift NM_001354898.2:c.72_75del NP_001341827.1:p.Lys24fs frameshift NM_001354899.2:c.147_150del NP_001341828.1:p.Lys49fs frameshift NM_001354900.2:c.-31_-28del 5 prime UTR NM_001354901.2:c.-31_-28del 5 prime UTR NM_001354902.2:c.177_180del NP_001341831.1:p.Lys59fs frameshift NM_001354903.2:c.147_150del NP_001341832.1:p.Lys49fs frameshift NM_001354904.2:c.72_75del NP_001341833.1:p.Lys24fs frameshift NM_001354905.2:c.-31_-28del 5 prime UTR NM_001354906.2:c.-889_-886del 5 prime UTR NC_000005.10:g.112766337_112766340del NC_000005.9:g.112102034_112102037del NG_008481.4:g.78817_78820del LRG_130:g.78817_78820del - Protein change
- K59fs, K49fs, K24fs
- Other names
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- Canonical SPDI
- NC_000005.10:112766334:AAACAA:AA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14091 | 14225 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2022 | RCV000129859.15 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV000502854.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 21, 2022 | RCV000497263.12 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 15, 2023 | RCV000552842.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 20, 2021 | RCV001778749.8 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2021 | RCV003162574.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV003743586.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV003997533.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial multiple polyposis syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002014983.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Comment:
Variant summary: APC c.147_150delACAA (p.Lys49AsnfsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: APC c.147_150delACAA (p.Lys49AsnfsX20) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251042 control chromosomes (gnomAD). c.147_150delACAA has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (e.g. Gomez-Fernandez_2009, Rivera_2011, Lorca_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774303.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This frameshift variant causes the premature termination of APC protein synthesis. In addition, it has been reported in individuals with colon polyps, attenuated adenomatous polyposis … (more)
This frameshift variant causes the premature termination of APC protein synthesis. In addition, it has been reported in individuals with colon polyps, attenuated adenomatous polyposis (AFAP) and familial adenomatous polyposis (FAP) in the published literature (PMID: 19531215 (2009), 20924072 (2011), 23159591 (2013), 26681312 (2015), 31285513 (2019)). Therefore, the variant is classified as pathogenic. (less)
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Pathogenic
(Oct 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000209574.5
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Gmez-Fernndez et al., 2009; Rivera et al., 2011); Frameshift … (more)
Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Gmez-Fernndez et al., 2009; Rivera et al., 2011); Frameshift 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: 26681312, 19531215, 20924072, 31285513) (less)
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Pathogenic
(Dec 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000184676.8
First in ClinVar: Aug 06, 2014 Last updated: Apr 15, 2023 |
Comment:
The c.147_150delACAA pathogenic mutation, located in coding exon 2 of the APC gene, results from a deletion of 4 nucleotides between positions 147 and 150, … (more)
The c.147_150delACAA pathogenic mutation, located in coding exon 2 of the APC gene, results from a deletion of 4 nucleotides between positions 147 and 150, causing a translational frameshift with a predicted alternate stop codon (p.K49Nfs*20). This mutation has been reported in multiple individuals with features of both familial adenomatous polyposis (FAP) and attenuated FAP (Gomez-Fernandez N et al. BMC Med. Genet. 2009 Jun 16;10:57; Rivera B et al. Ann. Oncol. 2011 Apr;22(4):903-9; Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). 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 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 2 are associated with an attenuated phenotype and may have reduced penetrance compared to classic familial adenomatous polyposis syndrome. Clinical correlation is advised. (less)
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Pathogenic
(Apr 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004044759.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Pathogenic
(Oct 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004196478.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000647180.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Lys49Asnfs*20) in the APC gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Lys49Asnfs*20) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colon polyps, attenuated adenomatous polyposis (AFAP) and familial adenomatous polyposis (FAP) (PMID: 19531215, 20924072, 26681312). ClinVar contains an entry for this variant (Variation ID: 141368). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Classic or attenuated familial adenomatous polyposis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004840103.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.147_150del (p.Lys49Asnfs*20) variant in the APC gene is located on the exon 3 and is predicted to cause shift of reading frame that introduces … (more)
The c.147_150del (p.Lys49Asnfs*20) variant in the APC gene is located on the exon 3 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Lys49Asnfs*20), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with familial adenomatous polyposis and attenuated adenomatous polyposis (PMID: 20924072, 31285513, 19531215, 26681312). Alterations that result in premature termination in the N-terminus of the APC protein are associated with an attenuated phenotype and may have incomplete penetrance compared to classic familial adenomatous polyposis syndrome (PMID: 9585611, 11257105). Loss-of-function variants of APC are known to be pathogenic (PMID: 26446593, 23159591, 31591141, 33769591). The variant is reported in ClinVar as pathogenic (ID: 141368). The variant is absent in the general population database (gnomAD). Therefore, the c.147_150del (p.Lys49Asnfs*20) variant of APC has been classified as pathogenic. (less)
Number of individuals with the variant: 2
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Pathogenic
(Jun 01, 2018)
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no assertion criteria provided
Method: clinical testing
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Familial adenomatous polyposis 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Molecular Oncology Laboratory, Hospital Clínico San Carlos
Accession: SCV000844923.1
First in ClinVar: Apr 22, 2019 Last updated: Apr 22, 2019 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000591015.3 First in ClinVar: Aug 28, 2017 Last updated: Apr 13, 2021 |
Comment:
The APC p.Lys49AsnfsX20 variant was identified in 2 of 436 proband chromosomes (frequency: 0.005) from individuals or families with FAP (Gomez-Fernandez 2009, Rivera 2011). The … (more)
The APC p.Lys49AsnfsX20 variant was identified in 2 of 436 proband chromosomes (frequency: 0.005) from individuals or families with FAP (Gomez-Fernandez 2009, Rivera 2011). The variant was also identified in HGMD, InSiGHT Colon Cancer Gene Variant Database, the ClinVar database (classified as a pathogenic variant by the Ambry Genetics), GeneInsight VariantWire database (1X, classified as “pathogenic” by a clinical laboratory), and UMD (12X).The p.Lys49AsnfsX20 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 49 and leads to a premature stop codon 20 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. 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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 01, 2021)
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no assertion criteria provided
Method: research
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Gastric cancer
Affected status: unknown
Allele origin:
germline
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Laboratory for Genotyping Development, RIKEN
Accession: SCV002758320.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
Mutational screening through comprehensive bioinformatics analysis to detect novel germline mutations in the APC gene in patients with familial adenomatous polyposis (FAP). | Ghadamyari F | Journal of clinical laboratory analysis | 2021 | PMID: 33769591 |
Gastric polyposis and desmoid tumours as a new familial adenomatous polyposis clinical variant associated with APC mutation at the extreme 3'-end. | Disciglio V | Journal of medical genetics | 2020 | PMID: 31591141 |
Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing. | Lorca V | Scientific reports | 2019 | PMID: 31285513 |
Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. | LaDuca H | PloS one | 2017 | PMID: 28152038 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary. | Papp J | Familial cancer | 2016 | PMID: 26446593 |
APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. | Kerr SE | The Journal of molecular diagnostics : JMD | 2013 | PMID: 23159591 |
Clinical and genetic characterization of classical forms of familial adenomatous polyposis: a Spanish population study. | Rivera B | Annals of oncology : official journal of the European Society for Medical Oncology | 2011 | PMID: 20924072 |
Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP. | Lagarde A | Journal of medical genetics | 2010 | PMID: 20685668 |
Molecular analysis of the APC and MUTYH genes in Galician and Catalonian FAP families: a different spectrum of mutations? | Gómez-Fernández N | BMC medical genetics | 2009 | PMID: 19531215 |
Mutational screening of the APC gene in Chilean families with familial adenomatous polyposis: nine novel truncating mutations. | De la Fuente MK | Diseases of the colon and rectum | 2007 | PMID: 17963004 |
The ABC of APC. | Fearnhead NS | Human molecular genetics | 2001 | PMID: 11257105 |
Genotype-phenotype correlations in attenuated adenomatous polyposis coli. | Soravia C | American journal of human genetics | 1998 | PMID: 9585611 |
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Text-mined citations for rs587781694 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.