VCV000376414.29 - ClinVar

NM_001349798.2(FBXW7):c.1393C>T (p.Arg465Cys)

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Pathogenic
Pathogenic (1)

This classification is based on the single submission received

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.

Somatic

Clinical impact

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Tier II (Potential) for Colorectal cancer

This classification is based on the single submission received

The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

Oncogenicity

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Oncogenic

This classification is based on the single submission received

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Variant Details

Identifiers

NM_001349798.2(FBXW7):c.1393C>T (p.Arg465Cys)

Variation ID: 376414 Accession: VCV000376414.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q31.3 4: 152328233 (GRCh38) [ NCBI UCSC ] 4: 153249385 (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	Mar 8, 2017	Apr 25, 2026	Oct 1, 2022
Somatic - Clinical impact	Nov 22, 2025	Nov 22, 2025	Oct 17, 2023
Somatic - Oncogenicity	Jan 3, 2026	Jan 3, 2026	Dec 29, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001349798.2:c.1393C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001336727.1:p.Arg465Cys	missense
NM_001013415.2:c.1039C>T	NP_001013433.1:p.Arg347Cys	missense
NM_018315.5:c.1153C>T	NP_060785.2:p.Arg385Cys	missense
NM_033632.3:c.1393C>T	NP_361014.1:p.Arg465Cys	missense
NC_000004.12:g.152328233G>A
NC_000004.11:g.153249385G>A
NG_029466.2:g.213641C>T
LRG_1141:g.213641C>T
LRG_1141t1:c.1393C>T	LRG_1141p1:p.Arg465Cys
LRG_1141t2:c.1153C>T	LRG_1141p2:p.Arg385Cys
LRG_1141t3:c.1039C>T	LRG_1141p3:p.Arg347Cys

... more HGVS ... less HGVS

Protein change

R465C, R347C, R385C

Other names

Canonical SPDI

NC_000004.12:152328232:G:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA16602851 dbSNP: rs867384286 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.
FBXW7		-	-	GRCh38 GRCh37	279	327

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.
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 1, 2022	RCV002512102.26

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.	Expand all rows Collapse all rows 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 (Oct 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV002821278.25 First in ClinVar: Jan 21, 2023 Last updated: Apr 25, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Comment:

Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in colorectal cancer, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 17646408, 17646409, 17909001, 23095493, 28963353). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 17909001, 25450649, 28963353, 37064111).

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Colorectal cancer	Tier II (Potential) - diagnostic - supports diagnosis (1)		Oct 17, 2023	RCV006254006.1
Neoplasm		Oncogenic criteria provided, single submitter	Dec 29, 2025	RCV006273730.1

Submissions - Somatic

Clinical impact Help The submitted somatic clinical impact 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)	Tumor type Help The tumor type 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.	Expand all rows Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Tier II (Potential) - Diagnostic - supports diagnosis (Oct 17, 2023) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Colorectal cancer	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007105720.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (7) PubMed: 17646408‚ 17646409‚ 17909001‚ 23095493‚ 25450649‚ 28963353‚ 37064111 Comment: show Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in colorectal cancer, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 17646408, 17646409, 17909001, 23095493, 28963353). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 17909001, 25450649, 28963353, 37064111). (less) Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Oncogenicity Help The submitted oncogenicity 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)	Tumor type Help The tumor type 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.	Expand all rows Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Oncogenic (Dec 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)	Neoplasm	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV007129541.1 First In ClinVar: Jan 03, 2026 Last updated: Jan 03, 2026	Publications: PubMed (2) PubMed: 17646409‚ 31161818 Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Comment:

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers.	Liu Y	Frontiers in oncology	2023	PMID: 37064111
FBXW7 Mutations Promote Cell Proliferation, Migration, and Invasion in Cervical Cancer.	Liu F	Genetic testing and molecular biomarkers	2019	PMID: 31161818
Somatic Superenhancer Duplications and Hotspot Mutations Lead to Oncogenic Activation of the KLF5 Transcription Factor.	Zhang X	Cancer discovery	2018	PMID: 28963353
FBXW7 mutation analysis and its correlation with clinicopathological features and prognosis in colorectal cancer patients.	Chang CC	The International journal of biological markers	2015	PMID: 25450649
FBXW7 is involved in Aurora B degradation.	Teng CL	Cell cycle (Georgetown, Tex.)	2012	PMID: 23095493
FBXW7/hCDC4 is a general tumor suppressor in human cancer.	Akhoondi S	Cancer research	2007	PMID: 17909001
FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.	O'Neil J	The Journal of experimental medicine	2007	PMID: 17646409
FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.	O'Neil J	The Journal of experimental medicine	2007	PMID: 17646409
The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia.	Thompson BJ	The Journal of experimental medicine	2007	PMID: 17646408

Text-mined citations for rs867384286 ...

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 Apr 26, 2026