VCV000052132.16 - ClinVar

NM_000059.4(BRCA2):c.6601del (p.Ser2201fs)

Germline

Top reviewed classifications are shown here.

Submission summary:

4 submissions

4 submitters

3 conditions

Reviewed by expert panel

Pathogenic

Sep 2016 by Evidence-based…

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

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.6601del (p.Ser2201fs)

Variation ID: 52132 Accession: VCV000052132.16

Type and length

Deletion, 1 bp

Location

Cytogenetic: 13q13.1 13: 32340952 (GRCh38) [ NCBI UCSC ] 13: 32915089 (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	Sep 24, 2016	Aug 11, 2024	Sep 8, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.6601del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Ser2201fs	frameshift
NM_000059.3:c.6601delT
NC_000013.11:g.32340956del
NC_000013.10:g.32915093del
NG_012772.3:g.30477del
LRG_293:g.30477del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000013.11:32340951:TTTTT:TTTT

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: CA024201 dbSNP: rs80359607 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	18967	19126

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	Mar 22, 2024	RCV000165788.13
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (2)	reviewed by expert panel	Sep 8, 2016	RCV000241208.12
Hereditary breast ovarian cancer syndrome	Pathogenic (1)	criteria provided, single submitter	Aug 16, 2022	RCV001388414.15

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 (Sep 08, 2016)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015)) Method: curation	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Accession: SCV000301073.2 First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016	Comment: Variant allele predicted to encode a truncated non-functional protein.
Pathogenic (Oct 02, 2015)	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge Accession: SCV000327473.4 First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022
Pathogenic (Aug 16, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001589392.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 20104584 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52132). This variant has not been … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52132). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser2201Leufs*5) 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). (less)
Pathogenic (Mar 22, 2024)	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: SCV000216533.7 First in ClinVar: Mar 24, 2015 Last updated: Aug 11, 2024	Publications: PubMed (2) PubMed: 21318380‚ 23704984 Comment: The c.6601delT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 6601, causing … (more) The c.6601delT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 6601, causing a translational frameshift with a predicted alternate stop codon (p.S2201Lfs*5). This variant has been identified in individuals at risk for hereditary breast and/or ovarian cancer (Hansen TV et al. Fam. Cancer 2011 Jun;10(2):207-12; Li J et al. Int. J. Cancer 2019 01;144(2):281-289). Based on microarray RNA profiling, the breast cancer of one woman carrying this alteration was classified as a luminal B tumor, a common subtype in BRCA2 germline mutation carriers (Larsen MJ et al. PLoS ONE 2013 May;8(5):e64268). This variant is also designated as 6825delT and c.6597delT in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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)

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52132). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser2201Leufs*5) 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).

Comment:

The c.6601delT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 6601, causing a translational frameshift with a predicted alternate stop codon (p.S2201Lfs*5). This variant has been identified in individuals at risk for hereditary breast and/or ovarian cancer (Hansen TV et al. Fam. Cancer 2011 Jun;10(2):207-12; Li J et al. Int. J. Cancer 2019 01;144(2):281-289). Based on microarray RNA profiling, the breast cancer of one woman carrying this alteration was classified as a luminal B tumor, a common subtype in BRCA2 germline mutation carriers (Larsen MJ et al. PLoS ONE 2013 May;8(5):e64268). This variant is also designated as 6825delT and c.6597delT in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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.

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
Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.	Larsen MJ	PloS one	2013	PMID: 23704984
Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations.	Hansen TV	Familial cancer	2011	PMID: 21318380
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 rs80359607 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.6601del (p.Ser2201fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80359607 ...