Variant summary: APC c.3258_3259delCC (p.Leu1087GlnfsX31) 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 250276 control chromosomes (gnomAD). c.3258_3259delCC has been reported in the literature in a colorectal cancer tumor sample (e.g. Christie_2013), but to our knowledge has not been reported in the germline of individuals affected with colorectal cancer or Familial Adenomatous Polyposis and no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.3258_3259del (p.Leu1087fs)
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.
(2)
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/Likely pathogenic
2
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.3258_3259del (p.Leu1087fs)
Variation ID: 1723265 Accession: VCV001723265.3
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 5q22.2 5: 112838852-112838853 (GRCh38) [ NCBI UCSC ] 5: 112174549-112174550 (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 Nov 19, 2022 May 1, 2024 Jan 11, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.3258_3259del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Leu1087fs frameshift NM_001127510.3:c.3258_3259del NP_001120982.1:p.Leu1087fs frameshift NM_001127511.3:c.3204_3205del NP_001120983.2:p.Leu1069fs frameshift NM_001354895.2:c.3258_3259del NP_001341824.1:p.Leu1087fs frameshift NM_001354896.2:c.3312_3313del NP_001341825.1:p.Leu1105fs frameshift NM_001354897.2:c.3288_3289del NP_001341826.1:p.Leu1097fs frameshift NM_001354898.2:c.3183_3184del NP_001341827.1:p.Leu1062fs frameshift NM_001354899.2:c.3174_3175del NP_001341828.1:p.Leu1059fs frameshift NM_001354900.2:c.3135_3136del NP_001341829.1:p.Leu1046fs frameshift NM_001354901.2:c.3081_3082del NP_001341830.1:p.Leu1028fs frameshift NM_001354902.2:c.2985_2986del NP_001341831.1:p.Leu996fs frameshift NM_001354903.2:c.2955_2956del NP_001341832.1:p.Leu986fs frameshift NM_001354904.2:c.2880_2881del NP_001341833.1:p.Leu961fs frameshift NM_001354905.2:c.2778_2779del NP_001341834.1:p.Leu927fs frameshift NM_001354906.2:c.2409_2410del NP_001341835.1:p.Leu804fs frameshift NM_001407446.1:c.3342_3343delCC NP_001394375.1:p.Leu1115Glnfs frameshift NM_001407447.1:c.3312_3313delCC NP_001394376.1:p.Leu1105Glnfs frameshift NM_001407448.1:c.3312_3313delCC NP_001394377.1:p.Leu1105Glnfs frameshift NM_001407449.1:c.3312_3313delCC NP_001394378.1:p.Leu1105Glnfs frameshift NM_001407450.1:c.3258_3259delCC NP_001394379.1:p.Leu1087Glnfs frameshift NM_001407451.1:c.3237_3238delCC NP_001394380.1:p.Leu1080Glnfs frameshift NM_001407452.1:c.3228_3229delCC NP_001394381.1:p.Leu1077Glnfs frameshift NM_001407453.1:c.3081_3082delCC NP_001394382.1:p.Leu1028Glnfs frameshift NM_001407454.1:c.3009_3010delCC NP_001394383.1:p.Leu1004Glnfs frameshift NM_001407455.1:c.3009_3010delCC NP_001394384.1:p.Leu1004Glnfs frameshift NM_001407456.1:c.3009_3010delCC NP_001394385.1:p.Leu1004Glnfs frameshift NM_001407457.1:c.3009_3010delCC NP_001394386.1:p.Leu1004Glnfs frameshift NM_001407458.1:c.2955_2956delCC NP_001394387.1:p.Leu986Glnfs frameshift NM_001407459.1:c.2955_2956delCC NP_001394388.1:p.Leu986Glnfs frameshift NM_001407460.1:c.2955_2956delCC NP_001394389.1:p.Leu986Glnfs frameshift NM_001407467.1:c.2871_2872delCC NP_001394396.1:p.Leu958Glnfs frameshift NM_001407469.1:c.2871_2872delCC NP_001394398.1:p.Leu958Glnfs frameshift NM_001407470.1:c.2409_2410delCC NP_001394399.1:p.Leu804Glnfs frameshift NM_001407471.1:c.2106_2107delCC NP_001394400.1:p.Leu703Glnfs frameshift NM_001407472.1:c.2106_2107delCC NP_001394401.1:p.Leu703Glnfs frameshift NR_176365.1:n.3093_3094delCC NR_176366.1:n.3512_3513delCC NC_000005.10:g.112838852_112838853del NC_000005.9:g.112174549_112174550del NG_008481.4:g.151332_151333del LRG_130:g.151332_151333del LRG_130t1:c.3258_3259del LRG_130p1:p.Leu1087Glnfs LRG_130t2:c.3258_3259del LRG_130p2:p.Leu1087Glnfs LRG_130t3:c.3258_3259del LRG_130p3:p.Leu1087Glnfs - Protein change
- L1028fs, L1046fs, L1059fs, L1062fs, L1069fs, L1087fs, L1097fs, L1105fs, L804fs, L927fs, L961fs, L986fs, L996fs
- Other names
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- Canonical SPDI
- NC_000005.10:112838851:CC:
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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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14965 | 15103 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
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Oct 10, 2022 | RCV002308541.1 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jan 11, 2023 | RCV003164528.2 |
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Oct 10, 2022)
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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
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002600385.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
Variant summary: APC c.3258_3259delCC (p.Leu1087GlnfsX31) 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.3258_3259delCC (p.Leu1087GlnfsX31) 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 250276 control chromosomes (gnomAD). c.3258_3259delCC has been reported in the literature in a colorectal cancer tumor sample (e.g. Christie_2013), but to our knowledge has not been reported in the germline of individuals affected with colorectal cancer or Familial Adenomatous Polyposis and no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
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Pathogenic
(Jan 11, 2023)
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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: SCV003866243.2
First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024 |
Comment:
The c.3258_3259delCC variant, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 3258 to 3259, … (more)
The c.3258_3259delCC variant, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 3258 to 3259, causing a translational frameshift with a predicted alternate stop codon (p.L1087Qfs*31). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 62% of the protein. However, premature stop codons are typically deleterious in nature, and a significant portion of the protein is affected (Ambry internal data).This alteration has been observed in at least one individual with a personal and/or family history that is consistent with APC-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
Comment:
Comment:
The c.3258_3259delCC variant, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 3258 to 3259, causing a translational frameshift with a predicted alternate stop codon (p.L1087Qfs*31). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 62% of the protein. However, premature stop codons are typically deleterious in nature, and a significant portion of the protein is affected (Ambry internal data).This alteration has been observed in at least one individual with a personal and/or family history that is consistent with APC-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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 summary: APC c.3258_3259delCC (p.Leu1087GlnfsX31) 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 250276 control chromosomes (gnomAD). c.3258_3259delCC has been reported in the literature in a colorectal cancer tumor sample (e.g. Christie_2013), but to our knowledge has not been reported in the germline of individuals affected with colorectal cancer or Familial Adenomatous Polyposis and no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
The c.3258_3259delCC variant, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 3258 to 3259, causing a translational frameshift with a predicted alternate stop codon (p.L1087Qfs*31). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 62% of the protein. However, premature stop codons are typically deleterious in nature, and a significant portion of the protein is affected (Ambry internal data).This alteration has been observed in at least one individual with a personal and/or family history that is consistent with APC-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/β-catenin signalling thresholds for tumourigenesis. | Christie M | Oncogene | 2013 | PMID: 23085758 |
Text-mined citations for this variant ...
HelpRecord last updated Jun 02, 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.