VCV000486786.11 - ClinVar

NM_000038.6(APC):c.4778del (p.Lys1593fs)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Familial adenomatous polyposis 1

Classification is based on the expert panel submission

Feb 2023 by ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Vari…

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000038.6(APC):c.4778del (p.Lys1593fs)

Variation ID: 486786 Accession: VCV000486786.11

Type and length

Deletion, 1 bp

Location

Cytogenetic: 5q22.2 5: 112176064 (GRCh37) [ NCBI UCSC ] 5: 112840367 (GRCh38) [ 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	Jan 1, 2018	Aug 11, 2024	Feb 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000038.6:c.4778del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000029.2:p.Lys1593fs	frameshift
NM_000038.5:c.4778del
NM_000038.5:c.4778delA
NM_001127510.3:c.4778del	NP_001120982.1:p.Lys1593fs	frameshift
NM_001127511.3:c.4724del	NP_001120983.2:p.Lys1575fs	frameshift
NM_001354895.2:c.4778del	NP_001341824.1:p.Lys1593fs	frameshift
NM_001354896.2:c.4832del	NP_001341825.1:p.Lys1611fs	frameshift
NM_001354897.2:c.4808del	NP_001341826.1:p.Lys1603fs	frameshift
NM_001354898.2:c.4703del	NP_001341827.1:p.Lys1568fs	frameshift
NM_001354899.2:c.4694del	NP_001341828.1:p.Lys1565fs	frameshift
NM_001354900.2:c.4655del	NP_001341829.1:p.Lys1552fs	frameshift
NM_001354901.2:c.4601del	NP_001341830.1:p.Lys1534fs	frameshift
NM_001354902.2:c.4505del	NP_001341831.1:p.Lys1502fs	frameshift
NM_001354903.2:c.4475del	NP_001341832.1:p.Lys1492fs	frameshift
NM_001354904.2:c.4400del	NP_001341833.1:p.Lys1467fs	frameshift
NM_001354905.2:c.4298del	NP_001341834.1:p.Lys1433fs	frameshift
NM_001354906.2:c.3929del	NP_001341835.1:p.Lys1310fs	frameshift
NC_000005.10:g.112840372del
NC_000005.9:g.112176069del
NG_008481.4:g.152852del
LRG_130:g.152852del

... more HGVS ... less HGVS

Protein change

K1492fs, K1502fs, K1568fs, K1593fs, K1603fs, K1310fs, K1467fs, K1565fs, K1534fs, K1611fs, K1433fs, K1552fs, K1575fs

Other names

NM_000038.6(APC):c.4778del
p.Lys1593fs

Canonical SPDI

NC_000005.10:112840366:AAAAAA:AAAAA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA658655953 dbSNP: rs1554086185 VarSome

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
Gene	OMIM	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	15918	16064

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.
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Jun 11, 2024	RCV000575274.4
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 7, 2023	RCV000657448.2
Familial adenomatous polyposis 1	Pathogenic (2)	reviewed by expert panel	Feb 26, 2023	RCV003148798.3

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.
Pathogenic (Feb 26, 2023) C Contributing to aggregate classification	reviewed by expert panel (ClinGen InSiGHT HCCP VCEP ACMG Specifications APC V1) Method: curation	Familial adenomatous polyposis 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel FDA Recognized Database Accession: SCV003836605.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e0829064-a90a-4c77-87cd-27b89477f04d Comment: The c.4778del p.(Lys1593Serfs57) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in … (more) The c.4778del p.(Lys1593Serfs57) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 2 probands meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting, Internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PS4_Supporting, PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). (less)

Pathogenic (Jun 11, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000675941.6 First in ClinVar: Jan 01, 2018 Last updated: Aug 11, 2024	Comment: The c.4778delA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 4778, causing … (more) The c.4778delA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 4778, causing a translational frameshift with a predicted alternate stop codon (p.K1593Sfs*57). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 47% 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. (less)

Pathogenic (Jan 11, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000779183.1 First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018	Comment: This deletion of one nucleotide in APC is denoted c.4778delA at the cDNA level and p.Lys1593SerfsX57 (K1593SfsX57) at the protein level. The normal sequence, with … (more) This deletion of one nucleotide in APC is denoted c.4778delA at the cDNA level and p.Lys1593SerfsX57 (K1593SfsX57) at the protein level. The normal sequence, with the base that is deleted in brackets, is CAAAAA[delA]GCCA. The deletion causes a frameshift which changes a Lysine to a Serine at codon 1593, and creates a premature stop codon at position 57 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic. (less)

Pathogenic (May 11, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004045076.2 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.

Pathogenic (May 07, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004219466.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: This frameshift variant alters the translational reading frame of the APC mRNA and causes the premature termination of APC protein synthesis. This variant has not … (more) This frameshift variant alters the translational reading frame of the APC mRNA and causes the premature termination of APC protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). To the best of our knowledge, the variant has not been reported in the published literature. Based on the available information, this variant is classified as pathogenic. (less)

Comment:

The c.4778del p.(Lys1593Serfs*57) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 2 probands meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting, Internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PS4_Supporting, PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).

Comment:

The c.4778delA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 4778, causing a translational frameshift with a predicted alternate stop codon (p.K1593Sfs*57). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 47% 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Comment:

This deletion of one nucleotide in APC is denoted c.4778delA at the cDNA level and p.Lys1593SerfsX57 (K1593SfsX57) at the protein level. The normal sequence, with the base that is deleted in brackets, is CAAAAA[delA]GCCA. The deletion causes a frameshift which changes a Lysine to a Serine at codon 1593, and creates a premature stop codon at position 57 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.

Comment:

This frameshift variant alters the translational reading frame of the APC mRNA and causes the premature termination of APC protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). To the best of our knowledge, the variant has not been reported in the published literature. Based on the available information, this variant is classified as pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e0829064-a90a-4c77-87cd-27b89477f04d	-	-	-	-

Text-mined citations for rs1554086185 ...

These 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 May 17, 2025

ClinVar Genomic variation as it relates to human health

NM_000038.6(APC):c.4778del (p.Lys1593fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554086185 ...