VCV000038228.17 - ClinVar

NM_000059.4(BRCA2):c.9294C>A (p.Tyr3098Ter)

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

Sep 2016 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.9294C>A (p.Tyr3098Ter)

Variation ID: 38228 Accession: VCV000038228.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32394726 (GRCh38) [ NCBI UCSC ] 13: 32968863 (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	Feb 25, 2025	Sep 8, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.9294C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Tyr3098Ter	nonsense
NC_000013.11:g.32394726C>A
NC_000013.10:g.32968863C>A
NG_012772.3:g.84247C>A
LRG_293:g.84247C>A
LRG_293t1:c.9294C>A	LRG_293p1:p.Tyr3098Ter
U43746.1:n.9522C>A

... more HGVS ... less HGVS

Protein change

Y3098*

Other names

9522C>A

Canonical SPDI

NC_000013.11:32394725:C:A

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: CA026093 dbSNP: rs80359200 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	19963	20125

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	Sep 8, 2016	RCV000031811.20
Hereditary breast ovarian cancer syndrome	Pathogenic (2)	criteria provided, single submitter	Jul 2, 2024	RCV000496360.17
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Mar 30, 2023	RCV002371799.10

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) C Contributing to aggregate classification	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: SCV000301375.2 First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016	Comment: Variant allele predicted to encode a truncated non-functional protein.
Pathogenic (Apr 16, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000786350.2 First in ClinVar: Nov 05, 2016 Last updated: Nov 05, 2016	Publications: PubMed (2) PubMed: 9667259‚ 15887246
Pathogenic (Mar 30, 2023) 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: SCV002686675.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 15131399‚ 28724667‚ 28993434‚ 29084914 Comment: The p.Y3098* pathogenic mutation (also known as c.9294C>A), located in coding exon 24 of the BRCA2 gene, results from a C to A substitution at … (more) The p.Y3098* pathogenic mutation (also known as c.9294C>A), located in coding exon 24 of the BRCA2 gene, results from a C to A substitution at nucleotide position 9294. This changes the amino acid from a tyrosine to a stop codon within coding exon 24. This mutation has been reported in serous ovarian cancer patients (Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24:326-333), and in several Chinese breast cancer patients (Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Wen WX et al. J. Med. Genet. 2018 Feb;55:97-103). 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 02, 2024) N Not contributing to aggregate classification	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: SCV001578430.5 First in ClinVar: May 10, 2021 Last updated: Feb 25, 2025	Publications: PubMed (3) PubMed: 20104584‚ 15131399‚ 29446198 Comment: This sequence change creates a premature translational stop signal (p.Tyr3098) 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.Tyr3098) 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 a personal or family history of BRCA2-related cancer (PMID: 15131399, 29446198). This variant is also known as 9522C>A. ClinVar contains an entry for this variant (Variation ID: 38228). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 01, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: inherited	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000965835.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019
Pathogenic (Oct 02, 2015) N Not contributing to aggregate classification	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: SCV000328101.4 First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022
Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004047722.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The stop gained (c.9294C>A) variant has been reported previously in patients affected with Breast-ovarian cancer, familial, 2 (Lubinski et. al., 2004; Rebbeck et. al., 2018). … (more) The stop gained (c.9294C>A) variant has been reported previously in patients affected with Breast-ovarian cancer, familial, 2 (Lubinski et. al., 2004; Rebbeck et. al., 2018). The c.9294C>A variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.9294C>A in BRCA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in BRCA2 are known to be pathogenic (Borg et. al., 2010). For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Breast carcinoma (present) Comment on clinical features: Clinical indication: Invasive carcinoma breast.
Pathogenic (May 29, 2002) N Not contributing to aggregate classification	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: SCV000147603.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Number of individuals with the variant: 1 Ethnicity/Population group: Western European, English
Pathogenic (Oct 25, 2011) N Not contributing to aggregate classification	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: SCV000054419.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014
Pathogenic (Jan 31, 2014) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000587996.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017

Comment:

The p.Y3098* pathogenic mutation (also known as c.9294C>A), located in coding exon 24 of the BRCA2 gene, results from a C to A substitution at nucleotide position 9294. This changes the amino acid from a tyrosine to a stop codon within coding exon 24. This mutation has been reported in serous ovarian cancer patients (Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24:326-333), and in several Chinese breast cancer patients (Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Wen WX et al. J. Med. Genet. 2018 Feb;55:97-103). 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:

This sequence change creates a premature translational stop signal (p.Tyr3098*) 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 a personal or family history of BRCA2-related cancer (PMID: 15131399, 29446198). This variant is also known as 9522C>A. ClinVar contains an entry for this variant (Variation ID: 38228). For these reasons, this variant has been classified as Pathogenic.

Comment:

The stop gained (c.9294C>A) variant has been reported previously in patients affected with Breast-ovarian cancer, familial, 2 (Lubinski et. al., 2004; Rebbeck et. al., 2018). The c.9294C>A variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.9294C>A in BRCA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in BRCA2 are known to be pathogenic (Borg et. al., 2010). For these reasons, this variant has been 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
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.	Rebbeck TR	Human mutation	2018	PMID: 29446198
Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer.	Labidi-Galy SI	Clinical cancer research : an official journal of the American Association for Cancer Research	2018	PMID: 29084914
Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia.	Wen WX	Journal of medical genetics	2018	PMID: 28993434
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.	Sun J	Clinical cancer research : an official journal of the American Association for Cancer Research	2017	PMID: 28724667
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
Contribution of BRCA1 and BRCA2 germ-line mutations to the incidence of breast cancer in young women: results from a prospective population-based study in France.	Bonadona V	Genes, chromosomes & cancer	2005	PMID: 15887246
Cancer variation associated with the position of the mutation in the BRCA2 gene.	Lubinski J	Familial cancer	2004	PMID: 15131399
Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk.	Frank TS	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	1998	PMID: 9667259

Text-mined citations for rs80359200 ...

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 28, 2025

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.9294C>A (p.Tyr3098Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80359200 ...