The p.R332* pathogenic mutation (also known as c.994C>T), located in coding exon 9 of the APC gene, results from a C to T substitution at nucleotide position 994. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been identified in many patients diagnosed with FAP or AFAP from various ethnicities (Soravia et al. Am J Hum Genet. 1998. 62:1290-1301; Gomez-Fernandez N et al. BMC Med Genet. 2009 Jun 16;10:57; Friedl W & Aretz S. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114; Chubb D et al. J. Clin. Oncol. 2015 Feb;33(5):426-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.994C>T (p.Arg332Ter)
Germline
Classification
Help
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.
(14)
Help
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.
Pathogenic
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000038.6(APC):c.994C>T (p.Arg332Ter)
Variation ID: 184937 Accession: VCV000184937.66
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q22.2 5: 112819026 (GRCh38) [ NCBI UCSC ] 5: 112154723 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Sep 24, 2016 Oct 20, 2024 Jul 23, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.994C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Arg332Ter nonsense NM_001127510.3:c.994C>T NP_001120982.1:p.Arg332Ter nonsense NM_001127511.3:c.940C>T NP_001120983.2:p.Arg314Ter nonsense NM_001354895.2:c.994C>T NP_001341824.1:p.Arg332Ter nonsense NM_001354896.2:c.994C>T NP_001341825.1:p.Arg332Ter nonsense NM_001354897.2:c.1024C>T NP_001341826.1:p.Arg342Ter nonsense NM_001354898.2:c.919C>T NP_001341827.1:p.Arg307Ter nonsense NM_001354899.2:c.910C>T NP_001341828.1:p.Arg304Ter nonsense NM_001354900.2:c.817C>T NP_001341829.1:p.Arg273Ter nonsense NM_001354901.2:c.817C>T NP_001341830.1:p.Arg273Ter nonsense NM_001354902.2:c.964-243C>T intron variant NM_001354903.2:c.934-243C>T intron variant NM_001354904.2:c.859-243C>T intron variant NM_001354905.2:c.757-243C>T intron variant NM_001354906.2:c.145C>T NP_001341835.1:p.Arg49Ter nonsense NC_000005.10:g.112819026C>T NC_000005.9:g.112154723C>T NG_008481.4:g.131506C>T LRG_130:g.131506C>T LRG_130t1:c.994C>T - Protein change
- R314*, R332*, R304*, R342*, R273*, R307*, R49*
- Other names
- -
- Canonical SPDI
- NC_000005.10:112819025:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
Help
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. |
|||
| APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14981 | 15119 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 11, 2023 | RCV000164280.13 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jul 23, 2024 | RCV000202243.39 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2024 | RCV000460182.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 18, 2018 | RCV000503333.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 4, 2022 | RCV002498813.3 | |
|
Inherited polyposis and early onset colorectal cancer - germline testing
|
Pathogenic (1) |
criteria provided, single submitter
|
May 29, 2024 | RCV004692773.1 |
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
Help
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
Help
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
Help
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000214907.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.R332* pathogenic mutation (also known as c.994C>T), located in coding exon 9 of the APC gene, results from a C to T substitution at … (more)
The p.R332* pathogenic mutation (also known as c.994C>T), located in coding exon 9 of the APC gene, results from a C to T substitution at nucleotide position 994. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been identified in many patients diagnosed with FAP or AFAP from various ethnicities (Soravia et al. Am J Hum Genet. 1998. 62:1290-1301; Gomez-Fernandez N et al. BMC Med Genet. 2009 Jun 16;10:57; Friedl W & Aretz S. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114; Chubb D et al. J. Clin. Oncol. 2015 Feb;33(5):426-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. (less)
|
|
|
Pathogenic
(Apr 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004044662.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
|
|
|
Pathogenic
(Jul 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000292448.15
First in ClinVar: Jul 24, 2016 Last updated: Sep 16, 2024 |
Comment:
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 … (more)
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 individuals with APC-related phenotypes (PMID: 9585611, 10094557, 11748858, 20223039, 16461775, 25559809); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34326862, 28010732, 30072583, 16461775, 1646175, 11001924, 20223039, 20924072, 16134147, 17411426, 11748858, 19531215, 23159591, 25559809, 22987206, 11317365, 11960572, 19793053, 22425061, 20105204, 25525159, 9585611, 28790112, 29691710, 10094557, 31461190, 33468868, 33294277, 36225625, 33309985, 33664379) (less)
|
|
|
Pathogenic
(Nov 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002062608.20
First in ClinVar: Jan 29, 2022 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 18, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916472.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: APC c.994C>T (p.Arg332X) 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.994C>T (p.Arg332X) 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. The variant was absent in 276792 control chromosomes (gnomAD). The variant, c.994C>T, has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Cao_2000, Friedl_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: yes
Allele origin:
germline
|
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499601.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
|
|
|
Pathogenic
(Jan 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Colorectal cancer
Hepatocellular carcinoma Desmoid disease, hereditary Familial adenomatous polyposis 1 Familial adenomatous polyposis 1 Gastric cancer Gastric adenocarcinoma and proximal polyposis of the stomach
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002812650.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Dec 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000887559.3
First in ClinVar: Dec 06, 2016 Last updated: Jan 06, 2024 |
Comment:
This nonsense variant causes the premature termination of APC protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the … (more)
This nonsense variant causes the premature termination of APC protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with familial adenomatous polyposis (FAP) (PMIDs: 19531215 (2009), 11748858 (2001), 10713886 (2000)), suspected FAP (PMID: 20223039 (2005)), attenuated FAP (PMIDs: 17411426 (2007), 9585611 (1998)), colorectal cancer (PMID: 25559809 (2015)), and Lynch-like syndrome (PMID: 33294277 (2020)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Dec 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537665.5
First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 10 of the APC gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 10 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with familial adenomatous polyposis, attenuated familial adenomatous polyposis, and colorectal cancer (PMID: 9585611, 10713886, 11001924, 11748858, 11317365, 16461775, 17411426, 19531215, 20223039, 23159591, 25590978). 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. (less)
|
|
|
Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000552518.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg332*) 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.Arg332*) 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 familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP) (PMID: 9585611, 11748858, 17411426, 19531215, 25559809). ClinVar contains an entry for this variant (Variation ID: 184937). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Inherited polyposis and early onset colorectal cancer - germline testing
Affected status: yes
Allele origin:
germline
|
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Accession: SCV005196389.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
Comment:
PVS1,PS4_Moderate,PM2_Supporting
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000591061.3 First in ClinVar: Aug 28, 2017 Last updated: Apr 13, 2021 |
Number of individuals with the variant: 5
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257040.2
First in ClinVar: Nov 20, 2015 Last updated: Dec 06, 2016 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Not Provided
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV002818448.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
Comment:
Variant classified as Pathogenic and reported on 10-29-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant classified as Pathogenic and reported on 10-29-2021 by Lab or GTR ID 500031. 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. (less)
Clinical Features:
Precocious puberty (present) , Colon cancer (present) , Abnormality of eye movement (present) , Hypermetropia (present) , Conductive hearing impairment (present) , Motor stereotypies (present) … (more)
Precocious puberty (present) , Colon cancer (present) , Abnormality of eye movement (present) , Hypermetropia (present) , Conductive hearing impairment (present) , Motor stereotypies (present) , Anxiety (present) , Depression (present) , Short attention span (present) , Feeding difficulties (present) , Gastrointestinal dysmotility (present) , Abnormal intestine morphology (present) , Abnormality of the bladder (present) , Tooth malposition (present) (less)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2021-10-29
Testing laboratory interpretation: Pathogenic
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
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 individuals with APC-related phenotypes (PMID: 9585611, 10094557, 11748858, 20223039, 16461775, 25559809); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34326862, 28010732, 30072583, 16461775, 1646175, 11001924, 20223039, 20924072, 16134147, 17411426, 11748858, 19531215, 23159591, 25559809, 22987206, 11317365, 11960572, 19793053, 22425061, 20105204, 25525159, 9585611, 28790112, 29691710, 10094557, 31461190, 33468868, 33294277, 36225625, 33309985, 33664379)
Comment:
Variant summary: APC c.994C>T (p.Arg332X) 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. The variant was absent in 276792 control chromosomes (gnomAD). The variant, c.994C>T, has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Cao_2000, Friedl_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This nonsense variant causes the premature termination of APC protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with familial adenomatous polyposis (FAP) (PMIDs: 19531215 (2009), 11748858 (2001), 10713886 (2000)), suspected FAP (PMID: 20223039 (2005)), attenuated FAP (PMIDs: 17411426 (2007), 9585611 (1998)), colorectal cancer (PMID: 25559809 (2015)), and Lynch-like syndrome (PMID: 33294277 (2020)). Based on the available information, this variant is classified as pathogenic.
Comment:
This variant changes 1 nucleotide in exon 10 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with familial adenomatous polyposis, attenuated familial adenomatous polyposis, and colorectal cancer (PMID: 9585611, 10713886, 11001924, 11748858, 11317365, 16461775, 17411426, 19531215, 20223039, 23159591, 25590978). 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.
Comment:
This sequence change creates a premature translational stop signal (p.Arg332*) 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 familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP) (PMID: 9585611, 11748858, 17411426, 19531215, 25559809). ClinVar contains an entry for this variant (Variation ID: 184937). For these reasons, this variant has been classified as Pathogenic.
Comment:
PVS1,PS4_Moderate,PM2_Supporting
Comment:
Variant classified as Pathogenic and reported on 10-29-2021 by Lab or GTR ID 500031. 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.
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. |
Comment:
The p.R332* pathogenic mutation (also known as c.994C>T), located in coding exon 9 of the APC gene, results from a C to T substitution at nucleotide position 994. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been identified in many patients diagnosed with FAP or AFAP from various ethnicities (Soravia et al. Am J Hum Genet. 1998. 62:1290-1301; Gomez-Fernandez N et al. BMC Med Genet. 2009 Jun 16;10:57; Friedl W & Aretz S. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114; Chubb D et al. J. Clin. Oncol. 2015 Feb;33(5):426-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
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 individuals with APC-related phenotypes (PMID: 9585611, 10094557, 11748858, 20223039, 16461775, 25559809); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34326862, 28010732, 30072583, 16461775, 1646175, 11001924, 20223039, 20924072, 16134147, 17411426, 11748858, 19531215, 23159591, 25559809, 22987206, 11317365, 11960572, 19793053, 22425061, 20105204, 25525159, 9585611, 28790112, 29691710, 10094557, 31461190, 33468868, 33294277, 36225625, 33309985, 33664379)
Comment:
Variant summary: APC c.994C>T (p.Arg332X) 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. The variant was absent in 276792 control chromosomes (gnomAD). The variant, c.994C>T, has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Cao_2000, Friedl_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This nonsense variant causes the premature termination of APC protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with familial adenomatous polyposis (FAP) (PMIDs: 19531215 (2009), 11748858 (2001), 10713886 (2000)), suspected FAP (PMID: 20223039 (2005)), attenuated FAP (PMIDs: 17411426 (2007), 9585611 (1998)), colorectal cancer (PMID: 25559809 (2015)), and Lynch-like syndrome (PMID: 33294277 (2020)). Based on the available information, this variant is classified as pathogenic.
Comment:
This variant changes 1 nucleotide in exon 10 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with familial adenomatous polyposis, attenuated familial adenomatous polyposis, and colorectal cancer (PMID: 9585611, 10713886, 11001924, 11748858, 11317365, 16461775, 17411426, 19531215, 20223039, 23159591, 25590978). 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.
Comment:
This sequence change creates a premature translational stop signal (p.Arg332*) 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 familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP) (PMID: 9585611, 11748858, 17411426, 19531215, 25559809). ClinVar contains an entry for this variant (Variation ID: 184937). For these reasons, this variant has been classified as Pathogenic.
Comment:
PVS1,PS4_Moderate,PM2_Supporting
Comment:
Variant classified as Pathogenic and reported on 10-29-2021 by Lab or GTR ID 500031. 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular screening and clinicopathologic characteristics of Lynch-like syndrome in a Chinese colorectal cancer cohort. | Xu HX | American journal of cancer research | 2020 | PMID: 33294277 |
| Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing. | Inra JA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25590978 |
| Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. | Chubb D | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25559809 |
| 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 |
| 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 |
| Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects. | Stekrova J | BMC medical genetics | 2007 | PMID: 17411426 |
| Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation. | Sieber OM | Gut | 2006 | PMID: 16461775 |
| Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients. | Friedl W | Hereditary cancer in clinical practice | 2005 | PMID: 20223039 |
| Molecular and clinical characteristics in 32 families affected with familial adenomatous polyposis. | Hutter P | Human mutation | 2001 | PMID: 11748858 |
| Nine novel APC mutations in Italian FAP patients. | Resta N | Human mutation | 2001 | PMID: 11317365 |
| Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q. | Lamlum H | Human molecular genetics | 2000 | PMID: 11001924 |
| APC mutation and phenotypic spectrum of Singapore familial adenomatous polyposis patients. | Cao X | European journal of human genetics : EJHG | 2000 | PMID: 10713886 |
| Genotype-phenotype correlations in attenuated adenomatous polyposis coli. | Soravia C | American journal of human genetics | 1998 | PMID: 9585611 |
| click to load more click to collapse | ||||
Text-mined citations for rs775126020 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.