VCV000038059.47 - ClinVar

NM_000059.4(BRCA2):c.6641dup (p.Tyr2215fs)

Germline

Top reviewed classifications are shown here.

Submission summary:

16 submissions

16 submitters

7 conditions

Reviewed by expert panel

Pathogenic

Apr 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.6641dup (p.Tyr2215fs)

Variation ID: 38059 Accession: VCV000038059.47

Type and length

Duplication, 1 bp

Location

Cytogenetic: 13q13.1 13: 32340995-32340996 (GRCh38) [ NCBI UCSC ] 13: 32915133 (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	Apr 1, 2014	Oct 20, 2024	Apr 22, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.6641dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Tyr2215fs	frameshift
NM_000059.3:c.6641dupC
NC_000013.11:g.32340996dup
NC_000013.10:g.32915133dup
NG_012772.3:g.30517dup
LRG_293:g.30517dup
U43746.1:n.6869_6870insC

... more HGVS ... less HGVS

Protein change

Y2215fs

Other names

6869insC

Canonical SPDI

NC_000013.11:32340995:C:CC

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

Breast Cancer Information Core (BIC) (BRCA2): 6869&base_change=ins C ClinGen: CA024243 dbSNP: rs80359613 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.
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (7)	reviewed by expert panel	Apr 22, 2016	RCV000031641.22
Hereditary breast ovarian cancer syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 25, 2024	RCV000045004.19
Hereditary cancer-predisposing syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 6, 2023	RCV000130476.19
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic (1)	criteria provided, single submitter	Apr 2, 2020	RCV001310133.9
Familial cancer of breast	Pathogenic (1)	criteria provided, single submitter	Aug 9, 2023	RCV003460524.1
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV003992164.7
BRCA2-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 29, 2024	RCV004732573.1

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 (Apr 22, 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: SCV000282433.1 First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016	Comment: Variant allele predicted to encode a truncated non-functional protein.
Pathogenic (Dec 09, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002536252.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The BRCA2 c.6641dupC (p.Y2215LfsX10) variant has been reported in heterozygosity in multiple individuals with breast cancer (PMID: 22366370, 22923021, 29446198, 33471991, among others). It is … (more) The BRCA2 c.6641dupC (p.Y2215LfsX10) variant has been reported in heterozygosity in multiple individuals with breast cancer (PMID: 22366370, 22923021, 29446198, 33471991, among others). It is also known as c.6641insC (p.Thr2214Asnfs*10) in the literature. This variant causes a frameshift at amino acid 2215 that results in premature termination 10 amino acids downstream. At this location, nonsense-mediated decay is predicted to occur, resulting in a loss of gene function. Loss of function variants in BRCA2 are known to be pathogenic (PMID: 29446198). This variant is not reported in the population database Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654), but has been reported in ClinVar (Variation ID: 38059). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (4) PubMed: 22366370‚ 22923021‚ 29446198‚ 33471991
Pathogenic (Apr 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499681.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
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: SCV000327481.4 First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022
Pathogenic (Aug 09, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004213686.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Mar 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004810672.7 First in ClinVar: Apr 15, 2024 Last updated: Oct 20, 2024	Comment: BRCA2: PVS1, PM2, PS4:Moderate Number of individuals with the variant: 1
Pathogenic (Oct 10, 2015)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000296601.2 First in ClinVar: Jun 24, 2016 Last updated: Jan 03, 2022	Publications: PubMed (2) PubMed: 26295337‚ 22366370 Indication for testing: Hereditary breast and ovarian cancer syndrome (HBOC)
Pathogenic (Sep 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001342838.3 First in ClinVar: Mar 25, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 22366370‚ 24156927‚ 29446198‚ 33471991 Comment: This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more) This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals with a personal or family history of prostate, breast, and/or ovarian cancer (PMID: 22366370, 24156927, 29446198, 33471991, doi.org/10.20471/LO.2023.51.01.02). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Jan 25, 2024)	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: SCV000073017.10 First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 20104584‚ 22366370‚ 22923021‚ 24156927 Comment: This sequence change creates a premature translational stop signal (p.Tyr2215Leufs10) in the BRCA2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Tyr2215Leufs10) 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 breast and/or ovarian cancer (PMID: 22366370, 22923021, 24156927). This variant is also known as c.6641insC (p.Thr2214Asnfs*10). ClinVar contains an entry for this variant (Variation ID: 38059). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004844287.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (4) PubMed: 22366370‚ 24156927‚ 29446198‚ 33471991 Comment: This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more) This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals with a personal or family history of prostate, breast, and/or ovarian cancer (PMID: 22366370, 24156927, 29446198, 33471991, doi.org/10.20471/LO.2023.51.01.02). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less) Number of individuals with the variant: 2
Pathogenic (Sep 20, 2022)	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: SCV000185344.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: The c.6641dupC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of C at position 6641, causing a translational … (more) The c.6641dupC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of C at position 6641, causing a translational frameshift with a predicted alternate stop codon within coding exon 10. This mutation has been reported in multiple families with hereditary breast and/or ovarian cancer (Levanat, S et al. Gene. 2012 May 1;498(2):169-76; Novakovic, S et al. Int J Oncol. 2012 Nov;41(5):1619-27; Rebbeck TR et al. Hum. Mutat. 2018 May;39(5):593-620). 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)
Pathogenic (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV005090050.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024
Pathogenic (Aug 26, 2022)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV002588905.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Pathogenic (Oct 29, 2001)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000146897.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Number of individuals with the variant: 1 Ethnicity/Population group: Western, Central/Eastern European
Pathogenic (Jan 15, 2006)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: not provided Allele origin: germline	Sharing Clinical Reports Project (SCRP) Accession: SCV000054248.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014
Pathogenic (Mar 29, 2024)	no assertion criteria provided Method: clinical testing	BRCA2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005342894.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The BRCA2 c.6641dupC variant is predicted to result in a frameshift and premature protein termination (p.Tyr2215Leufs10). This variant was reported in individuals with breast cancer … (more) The BRCA2 c.6641dupC variant is predicted to result in a frameshift and premature protein termination (p.Tyr2215Leufs10). This variant was reported in individuals with breast cancer (Levanat et al. 2012. PubMed ID: 22366370; Krivokuca et al. 2021. PubMed ID: 34284872). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in BRCA2 are expected to be pathogenic. This variant has been interpreted as pathogenic by an expert curation panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38059/). This variant is interpreted as pathogenic. (less)
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Comment:

This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals with a personal or family history of prostate, breast, and/or ovarian cancer (PMID: 22366370, 24156927, 29446198, 33471991, doi.org/10.20471/LO.2023.51.01.02). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Tyr2215Leufs*10) 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 breast and/or ovarian cancer (PMID: 22366370, 22923021, 24156927). This variant is also known as c.6641insC (p.Thr2214Asnfs*10). ClinVar contains an entry for this variant (Variation ID: 38059). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.6641dupC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of C at position 6641, causing a translational frameshift with a predicted alternate stop codon within coding exon 10. This mutation has been reported in multiple families with hereditary breast and/or ovarian cancer (Levanat, S et al. Gene. 2012 May 1;498(2):169-76; Novakovic, S et al. Int J Oncol. 2012 Nov;41(5):1619-27; Rebbeck TR et al. Hum. Mutat. 2018 May;39(5):593-620). 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.

Comment:

The BRCA2 c.6641dupC variant is predicted to result in a frameshift and premature protein termination (p.Tyr2215Leufs*10). This variant was reported in individuals with breast cancer (Levanat et al. 2012. PubMed ID: 22366370; Krivokuca et al. 2021. PubMed ID: 34284872). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in BRCA2 are expected to be pathogenic. This variant has been interpreted as pathogenic by an expert curation panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38059/). This variant is interpreted 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
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.	Rebbeck TR	Human mutation	2018	PMID: 29446198
Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer.	Tea MK	Maturitas	2014	PMID: 24156927
Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families.	Novaković S	International journal of oncology	2012	PMID: 22923021
Three novel BRCA1/BRCA2 mutations in breast/ovarian cancer families in Croatia.	Levanat S	Gene	2012	PMID: 22366370
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 rs80359613 ...

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.6641dup (p.Tyr2215fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80359613 ...