VCV000233155.21 - ClinVar

NM_000059.4(BRCA2):c.5197_5198del (p.Ser1733fs)

Germline

Reviewed by expert panel

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

Pathogenic

for Breast-ovarian cancer, familial, susceptibility to, 2

Classification is based on the expert panel submission

Dec 2017 by Evidence-based Network for the Interpretation of Germline M…

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

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.5197_5198del (p.Ser1733fs)

Variation ID: 233155 Accession: VCV000233155.21

Type and length

Microsatellite, 2 bp

Location

Cytogenetic: 13q13.1 13: 32339548-32339549 (GRCh38) [ NCBI UCSC ] 13: 32913685-32913686 (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	May 29, 2016	Feb 15, 2026	Dec 15, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.5197_5198del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Ser1733fs	frameshift
NM_000059.3:c.5197_5198delTC
NC_000013.11:g.32339548TC[2]
NC_000013.10:g.32913685TC[2]
NG_012772.3:g.29069TC[2]
LRG_293:g.29069TC[2]
LRG_293t1:c.5197_5198del

... more HGVS ... less HGVS

Protein change

S1733fs

Other names

Canonical SPDI

NC_000013.11:32339547:TCTCTC:TCTC

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: CA10579646 dbSNP: rs876660228 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.
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	21455	21622

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	Sep 22, 2022	RCV000218209.11
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 6, 2023	RCV000657265.10
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (1)	reviewed by expert panel	Dec 15, 2017	RCV000661529.9
Hereditary breast ovarian cancer syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 15, 2025	RCV000700708.21
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic (1)	criteria provided, single submitter	Apr 2, 2020	RCV001310155.9

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 (Dec 15, 2017) C Contributing to aggregate classification	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2017-06-29))	Breast-ovarian cancer, familial, susceptibility to, 2	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Study: ENIGMA Accession: SCV000783819.1 First in ClinVar: Jul 13, 2018 Last updated: Jul 13, 2018	Comment: show Variant allele predicted to encode a truncated non-functional protein. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (Apr 02, 2020) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Breast-ovarian cancer, familial, susceptibility to, 1	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499733.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Jan 06, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria)	not provided	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004219675.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (3) PubMed: 28888541‚ 29446198‚ 29907814 Comment: show This frameshift variant alters the translational reading frame of the BRCA2 mRNA and is predicted to cause the premature termination of BRCA2 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 a personal or family history of breast and/or ovarian cancer (PMIDs: 29907814 (2018), 29446198 (2018), and 28888541 (2017)). Based on the available information, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Sep 22, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV000277472.5 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Comment: show The c.5197_5198delTC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 5197 to 5198, causing a translational frameshift with a predicted alternate stop codon (p.S1733Rfs*9). 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (May 15, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary breast ovarian cancer syndrome	GeneKor MSA Accession: SCV006311222.1 First in ClinVar: Aug 30, 2025 Last updated: Aug 30, 2025	Publications: PubMed (2) PubMed: 20104584‚ 29446198 Comment: show This variant is a deletion of 2 nucleotides in exon 11 of the BRCA2 mRNA c.(5197_5198delTC), causing a frameshift after codon 1733 and the creation of a premature translation stop signal 9 amino acid residues later p.(Ser1733Argfs*9). This is expected to result in an absent or disrupted protein product. Truncating variants in the BRCA2 gene are known to be pathogenic (PMID:20104584). This variant is not present in population databases (rs876660228).This sequence change has been reported in a family with an increasing risk of breast and ovarian cancer (PMID:29446198). ClinVar contains entries for this variant where is listed as pathogenic (VCV000233155.19). Based on the classification criteria set by the ACMG and AMP (PMID:25741868), this variant has been classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Nov 11, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hereditary breast ovarian cancer syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000829475.9 First in ClinVar: Oct 10, 2018 Last updated: Feb 15, 2026	Publications: PubMed (3) PubMed: 20104584‚ 28492532‚ 29446198 Comment: show This sequence change creates a premature translational stop signal (p.Ser1733Argfs*9) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with an increasing risk of breast and ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 233155). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Nov 21, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000778996.1 First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018	Comment: show This deletion of two nucleotides in BRCA2 is denoted c.5197_5198delTC at the cDNA level and p.Ser1733ArgfsX9 (S1733RfsX9) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TCTC[delTC]CGAA. The deletion causes a frameshift which changes a Serine to an Arginine at codon 1733, and creates a premature stop codon at position 9 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

This frameshift variant alters the translational reading frame of the BRCA2 mRNA and is predicted to cause the premature termination of BRCA2 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 a personal or family history of breast and/or ovarian cancer (PMIDs: 29907814 (2018), 29446198 (2018), and 28888541 (2017)). Based on the available information, this variant is classified as pathogenic.

Comment:

The c.5197_5198delTC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 5197 to 5198, causing a translational frameshift with a predicted alternate stop codon (p.S1733Rfs*9). 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 a deletion of 2 nucleotides in exon 11 of the BRCA2 mRNA c.(5197_5198delTC), causing a frameshift after codon 1733 and the creation of a premature translation stop signal 9 amino acid residues later p.(Ser1733Argfs*9). This is expected to result in an absent or disrupted protein product. Truncating variants in the BRCA2 gene are known to be pathogenic (PMID:20104584). This variant is not present in population databases (rs876660228).This sequence change has been reported in a family with an increasing risk of breast and ovarian cancer (PMID:29446198). ClinVar contains entries for this variant where is listed as pathogenic (VCV000233155.19). Based on the classification criteria set by the ACMG and AMP (PMID:25741868), this variant has been classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Ser1733Argfs*9) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with an increasing risk of breast and ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 233155). For these reasons, this variant has been classified as Pathogenic.

Comment:

This deletion of two nucleotides in BRCA2 is denoted c.5197_5198delTC at the cDNA level and p.Ser1733ArgfsX9 (S1733RfsX9) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TCTC[delTC]CGAA. The deletion causes a frameshift which changes a Serine to an Arginine at codon 1733, and creates a premature stop codon at position 9 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The germline mutational landscape of BRCA1 and BRCA2 in Brazil.	Palmero EI	Scientific reports	2018	PMID: 29907814
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.	Rebbeck TR	Human mutation	2018	PMID: 29446198
Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls.	Lilyquist J	Gynecologic oncology	2017	PMID: 28888541
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.	Borg A	Human mutation	2010	PMID: 20104584

Text-mined citations for rs876660228 ...

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 Feb 15, 2026