Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified as DM in HGMD - it has been seen in one patient with colorectal adenoma and one unaffected patient. It has been classified with 1 star as VUS by 4 sumitters (GeneDx, Invitae, CSER_CC_NCGL, Biesecker lab) and Likely benign by 1 (Ambry). MaxMAF is 0.02% in ExAC (high for disease prevalence).
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.3479C>A (p.Thr1160Lys)
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.
(17)
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.
Conflicting classifications of pathogenicity
Uncertain significance(8); Benign(1); Likely benign(5)
Uncertain significance(8); Benign(1); Likely benign(5)
17
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000038.6(APC):c.3479C>A (p.Thr1160Lys)
Variation ID: 41503 Accession: VCV000041503.45
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q22.2 5: 112839073 (GRCh38) [ NCBI UCSC ] 5: 112174770 (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 Apr 12, 2013 Dec 14, 2024 Sep 23, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.3479C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Thr1160Lys missense NM_001127510.3:c.3479C>A NP_001120982.1:p.Thr1160Lys missense NM_001127511.3:c.3425C>A NP_001120983.2:p.Thr1142Lys missense NM_001354895.2:c.3479C>A NP_001341824.1:p.Thr1160Lys missense NM_001354896.2:c.3533C>A NP_001341825.1:p.Thr1178Lys missense NM_001354897.2:c.3509C>A NP_001341826.1:p.Thr1170Lys missense NM_001354898.2:c.3404C>A NP_001341827.1:p.Thr1135Lys missense NM_001354899.2:c.3395C>A NP_001341828.1:p.Thr1132Lys missense NM_001354900.2:c.3356C>A NP_001341829.1:p.Thr1119Lys missense NM_001354901.2:c.3302C>A NP_001341830.1:p.Thr1101Lys missense NM_001354902.2:c.3206C>A NP_001341831.1:p.Thr1069Lys missense NM_001354903.2:c.3176C>A NP_001341832.1:p.Thr1059Lys missense NM_001354904.2:c.3101C>A NP_001341833.1:p.Thr1034Lys missense NM_001354905.2:c.2999C>A NP_001341834.1:p.Thr1000Lys missense NM_001354906.2:c.2630C>A NP_001341835.1:p.Thr877Lys missense NC_000005.10:g.112839073C>A NC_000005.9:g.112174770C>A NG_008481.4:g.151553C>A LRG_130:g.151553C>A LRG_130t1:c.3479C>A - Protein change
- T1160K, T1142K, T1034K, T1069K, T1101K, T1170K, T1000K, T1059K, T1178K, T1119K, T1132K, T1135K, T877K
- Other names
-
p.T1160K:ACA>AAA
- Canonical SPDI
- NC_000005.10:112839072:C:A
-
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.
-
Exome Aggregation Consortium (ExAC) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00014
The Genome Aggregation Database (gnomAD) 0.00017
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
- 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 |
15028 | 15166 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Aug 3, 2023 | RCV000034385.20 | |
| Uncertain significance (1) |
no assertion criteria provided
|
Jun 1, 2014 | RCV000148371.10 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Apr 19, 2023 | RCV000130655.27 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 30, 2024 | RCV000204291.26 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
May 24, 2024 | RCV000235094.22 | |
|
APC-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Aug 30, 2024 | RCV003407396.5 |
| Uncertain significance (1) |
criteria provided, single submitter
|
Sep 23, 2024 | RCV003996153.3 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jan 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000538297.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified as DM in HGMD - it has been seen in one patient with colorectal adenoma and one unaffected patient. It has been classified with 1 star as VUS by 4 sumitters (GeneDx, Invitae, CSER_CC_NCGL, Biesecker lab) and Likely benign by 1 (Ambry). MaxMAF is 0.02% in ExAC (high for disease prevalence). (less)
Method: Genome/Exome Filtration
|
|
|
Benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001136903.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Uncertain significance
(Jan 27, 2022)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002533780.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The APC c.3479C>A (p.T1160K) variant has been reported in individuals with multiple colorectal adenomas and/or colorectal cancer (PMID: 18199528, 29212164). It was observed in 30/128808 … (more)
The APC c.3479C>A (p.T1160K) variant has been reported in individuals with multiple colorectal adenomas and/or colorectal cancer (PMID: 18199528, 29212164). It was observed in 30/128808 chromosomes of the Non-Finnish European subpopulation, with no homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 41503). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
|
Uncertain significance
(Nov 24, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000487797.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
|
|
|
Uncertain significance
(Jun 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209515.17
First in ClinVar: Apr 12, 2013 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal history of colorectal adenomas or colorectal … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal history of colorectal adenomas or colorectal cancer (Azzopardi et al., 2008; Raskin et al., 2017); This variant is associated with the following publications: (PMID: 33918692, Biswas2021[abstract], 22703879, 25637381, 21859464, 18199528, 27150160, 27600092, 29212164, 28873162, 30709382, 35128723, 26580448, 35145771) (less)
|
|
|
Likely benign
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018831.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
|
|
|
Uncertain significance
(Jun 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003826838.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Likely benign
(May 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916470.4
First in ClinVar: Jun 03, 2019 Last updated: Aug 11, 2024 |
Comment:
Variant summary: APC c.3479C>A (p.Thr1160Lys) results in a non-conservative amino acid change located in the one of the 15 residue repeat domains (IPR009240) of the … (more)
Variant summary: APC c.3479C>A (p.Thr1160Lys) results in a non-conservative amino acid change located in the one of the 15 residue repeat domains (IPR009240) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 1613950 control chromosomes, predominantly at a frequency of 0.00048 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05). c.3479C>A has been reported in the literature in individuals affected with non-FAP non-MAP colorectal adenomas (example, Azzopardi 2008), in a family with colorectal cancer without polyps (example, Raskin 2017) and as a VUS in settings of multigene panel testing performed in an individual with Serrated Polyposis Syndrome (SPS) (example, Murphy_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22703879, 18199528, 26580448, 29212164, 35128723). ClinVar contains an entry for this variant (Variation ID: 41503). Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Likely benign
(Aug 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000600083.4
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
|
|
|
Uncertain significance
(Jun 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227110.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
BS1
Number of individuals with the variant: 3
|
|
|
Likely benign
(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: SCV000259359.12
First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024 |
|
|
|
Uncertain significance
(Apr 19, 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: SCV000681610.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with lysine at codon 1160 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with lysine at codon 1160 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual each affected with familial adenomatous polyposis (PMID: 18199528), colorectal cancer (PMID: 29212164), serrated polyposis syndrome (PMID: 35128723), breast cancer (PMID: 29684080) and in an individual(s) with an unspecified cancer (PMID: 28873162). This variant has also been observed in multiple individuals in the general population who were selected for phenotypes not directly related to cancer (PMID: 22703879, 25637381). This variant has been identified in 32/282180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Likely benign
(Nov 29, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185540.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Uncertain Significance
(Sep 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Classic or attenuated familial adenomatous polyposis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004839820.2
First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces threonine with lysine at codon 1160 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with lysine at codon 1160 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual each affected with familial adenomatous polyposis (PMID: 18199528), colorectal cancer (PMID: 29212164), serrated polyposis syndrome (PMID: 35128723), breast cancer (PMID: 29684080) and in an individual(s) with an unspecified cancer (PMID: 28873162). This variant has also been observed in multiple individuals in the general population who were selected for phenotypes not directly related to cancer (PMID: 22703879, 25637381). This variant has been identified in 32/282180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 54
Zygosity: Single Heterozygote
|
|
|
variant of unknown significance
(Jul 13, 2012)
|
no assertion criteria provided
Method: research
|
not provided
Affected status: no
Allele origin:
germline
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043123.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Uncertain significance.
Number of individuals with the variant: 1
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
|
|
|
Uncertain significance
(Aug 30, 2024)
|
no assertion criteria provided
Method: clinical testing
|
APC-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004115157.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The APC c.3479C>A variant is predicted to result in the amino acid substitution p.Thr1160Lys. This variant was reported in multiple individuals with colorectal adenoma, but … (more)
The APC c.3479C>A variant is predicted to result in the amino acid substitution p.Thr1160Lys. This variant was reported in multiple individuals with colorectal adenoma, but was also present in one unaffected 48 year old family member (Azzopardi et al. 2008. PubMed ID: 18199528; Table S1, Minde et al. 2011. PubMed ID: 21859464; Raskin et al. 2017. PubMed ID: 29212164). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112174770-C-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/41503/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
|
|
Uncertain significance
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Colorectal adenoma
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190064.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Comment:
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal history of colorectal adenomas or colorectal cancer (Azzopardi et al., 2008; Raskin et al., 2017); This variant is associated with the following publications: (PMID: 33918692, Biswas2021[abstract], 22703879, 25637381, 21859464, 18199528, 27150160, 27600092, 29212164, 28873162, 30709382, 35128723, 26580448, 35145771)
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Comment:
Variant summary: APC c.3479C>A (p.Thr1160Lys) results in a non-conservative amino acid change located in the one of the 15 residue repeat domains (IPR009240) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 1613950 control chromosomes, predominantly at a frequency of 0.00048 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05). c.3479C>A has been reported in the literature in individuals affected with non-FAP non-MAP colorectal adenomas (example, Azzopardi 2008), in a family with colorectal cancer without polyps (example, Raskin 2017) and as a VUS in settings of multigene panel testing performed in an individual with Serrated Polyposis Syndrome (SPS) (example, Murphy_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22703879, 18199528, 26580448, 29212164, 35128723). ClinVar contains an entry for this variant (Variation ID: 41503). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
BS1
Comment:
This missense variant replaces threonine with lysine at codon 1160 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual each affected with familial adenomatous polyposis (PMID: 18199528), colorectal cancer (PMID: 29212164), serrated polyposis syndrome (PMID: 35128723), breast cancer (PMID: 29684080) and in an individual(s) with an unspecified cancer (PMID: 28873162). This variant has also been observed in multiple individuals in the general population who were selected for phenotypes not directly related to cancer (PMID: 22703879, 25637381). This variant has been identified in 32/282180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
This missense variant replaces threonine with lysine at codon 1160 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual each affected with familial adenomatous polyposis (PMID: 18199528), colorectal cancer (PMID: 29212164), serrated polyposis syndrome (PMID: 35128723), breast cancer (PMID: 29684080) and in an individual(s) with an unspecified cancer (PMID: 28873162). This variant has also been observed in multiple individuals in the general population who were selected for phenotypes not directly related to cancer (PMID: 22703879, 25637381). This variant has been identified in 32/282180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Converted during submission to Uncertain significance.
Comment:
The APC c.3479C>A variant is predicted to result in the amino acid substitution p.Thr1160Lys. This variant was reported in multiple individuals with colorectal adenoma, but was also present in one unaffected 48 year old family member (Azzopardi et al. 2008. PubMed ID: 18199528; Table S1, Minde et al. 2011. PubMed ID: 21859464; Raskin et al. 2017. PubMed ID: 29212164). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112174770-C-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/41503/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified as DM in HGMD - it has been seen in one patient with colorectal adenoma and one unaffected patient. It has been classified with 1 star as VUS by 4 sumitters (GeneDx, Invitae, CSER_CC_NCGL, Biesecker lab) and Likely benign by 1 (Ambry). MaxMAF is 0.02% in ExAC (high for disease prevalence).
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal history of colorectal adenomas or colorectal cancer (Azzopardi et al., 2008; Raskin et al., 2017); This variant is associated with the following publications: (PMID: 33918692, Biswas2021[abstract], 22703879, 25637381, 21859464, 18199528, 27150160, 27600092, 29212164, 28873162, 30709382, 35128723, 26580448, 35145771)
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Comment:
Variant summary: APC c.3479C>A (p.Thr1160Lys) results in a non-conservative amino acid change located in the one of the 15 residue repeat domains (IPR009240) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 1613950 control chromosomes, predominantly at a frequency of 0.00048 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05). c.3479C>A has been reported in the literature in individuals affected with non-FAP non-MAP colorectal adenomas (example, Azzopardi 2008), in a family with colorectal cancer without polyps (example, Raskin 2017) and as a VUS in settings of multigene panel testing performed in an individual with Serrated Polyposis Syndrome (SPS) (example, Murphy_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22703879, 18199528, 26580448, 29212164, 35128723). ClinVar contains an entry for this variant (Variation ID: 41503). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
BS1
Comment:
This missense variant replaces threonine with lysine at codon 1160 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual each affected with familial adenomatous polyposis (PMID: 18199528), colorectal cancer (PMID: 29212164), serrated polyposis syndrome (PMID: 35128723), breast cancer (PMID: 29684080) and in an individual(s) with an unspecified cancer (PMID: 28873162). This variant has also been observed in multiple individuals in the general population who were selected for phenotypes not directly related to cancer (PMID: 22703879, 25637381). This variant has been identified in 32/282180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
This missense variant replaces threonine with lysine at codon 1160 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual each affected with familial adenomatous polyposis (PMID: 18199528), colorectal cancer (PMID: 29212164), serrated polyposis syndrome (PMID: 35128723), breast cancer (PMID: 29684080) and in an individual(s) with an unspecified cancer (PMID: 28873162). This variant has also been observed in multiple individuals in the general population who were selected for phenotypes not directly related to cancer (PMID: 22703879, 25637381). This variant has been identified in 32/282180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Converted during submission to Uncertain significance.
Comment:
The APC c.3479C>A variant is predicted to result in the amino acid substitution p.Thr1160Lys. This variant was reported in multiple individuals with colorectal adenoma, but was also present in one unaffected 48 year old family member (Azzopardi et al. 2008. PubMed ID: 18199528; Table S1, Minde et al. 2011. PubMed ID: 21859464; Raskin et al. 2017. PubMed ID: 29212164). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112174770-C-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/41503/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Germline variant testing in serrated polyposis syndrome. | Murphy A | Journal of gastroenterology and hepatology | 2022 | PMID: 35128723 |
| Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. | Yehia L | PLoS genetics | 2018 | PMID: 29684080 |
| Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort. | Raskin L | Oncotarget | 2017 | PMID: 29212164 |
| Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
| Germline Mutations in Predisposition Genes in Pediatric Cancer. | Zhang J | The New England journal of medicine | 2015 | PMID: 26580448 |
| Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
| Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
| Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
| Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer? | Minde DP | Molecular cancer | 2011 | PMID: 21859464 |
| Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. | Azzopardi D | Cancer research | 2008 | PMID: 18199528 |
Text-mined citations for rs201004111 ...
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Record last updated Dec 22, 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.