VCV000096801.15 - ClinVar

NM_000059.4(BRCA2):c.3939C>G (p.Tyr1313Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

7 submissions

7 submitters

4 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.3939C>G (p.Tyr1313Ter)

Variation ID: 96801 Accession: VCV000096801.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32338294 (GRCh38) [ NCBI UCSC ] 13: 32912431 (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	May 1, 2024	Sep 8, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.3939C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Tyr1313Ter	nonsense
NC_000013.11:g.32338294C>G
NC_000013.10:g.32912431C>G
NG_012772.3:g.27815C>G
LRG_293:g.27815C>G
LRG_293t1:c.3939C>G	LRG_293p1:p.Tyr1313Ter
U43746.1:n.4167C>G

... more HGVS ... less HGVS

Protein change

Y1313*

Other names

4167C>G

Canonical SPDI

NC_000013.11:32338293:C:G

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: CA019246 dbSNP: rs80358641 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	18962	19121

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 (3)	reviewed by expert panel	Sep 8, 2016	RCV000082922.5
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Jun 2, 2021	RCV000567978.3
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 21, 2017	RCV000520208.3
Hereditary breast ovarian cancer syndrome	Pathogenic (1)	criteria provided, single submitter	Oct 10, 2023	RCV001388924.7

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: SCV000300687.2 First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016	Comment: Variant allele predicted to encode a truncated non-functional protein.
Pathogenic (May 05, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000618441.2 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Comment: This variant is denoted BRCA2 c.3939C>G at the cDNA level and p.Tyr1313Ter (Y1313X) at the protein level. Using alternate nomenclature, this variant would be defined … (more) This variant is denoted BRCA2 c.3939C>G at the cDNA level and p.Tyr1313Ter (Y1313X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 4167C>G. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic. (less)
Pathogenic (Nov 21, 2017)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000887806.2 First in ClinVar: Dec 19, 2017 Last updated: Jan 01, 2022
Pathogenic (Oct 10, 2023)	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: SCV001590078.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 20104584‚ 16168118‚ 29446198‚ 30154229 Comment: This sequence change creates a premature translational stop signal (p.Tyr1313) 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.Tyr1313) 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 personal and/or family history of breast and/or ovarian cancers (PMID: 16168118, 29446198, 30154229). ClinVar contains an entry for this variant (Variation ID: 96801). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 02, 2021)	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: SCV000665399.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 16168118 Comment: The p.Y1313* pathogenic mutation (also known as c.3939C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at … (more) The p.Y1313* pathogenic mutation (also known as c.3939C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 3939. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This mutation has previously been reported in a Czech family with two cases of ovarian cancer (Pohlreich P et al. Breast Cancer Res. 2005 Jul;7:R728-36). In addition to the clinical data presented in the literature, his 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 (Dec 23, 2003)	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: SCV000146340.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Number of individuals with the variant: 1 Ethnicity/Population group: Latin American, Caribbean
Pathogenic (Nov 19, 2008)	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: SCV000114996.3 First in ClinVar: Feb 09, 2014 Last updated: Sep 27, 2014

Comment:

This variant is denoted BRCA2 c.3939C>G at the cDNA level and p.Tyr1313Ter (Y1313X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 4167C>G. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Tyr1313*) 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 personal and/or family history of breast and/or ovarian cancers (PMID: 16168118, 29446198, 30154229). ClinVar contains an entry for this variant (Variation ID: 96801). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Y1313* pathogenic mutation (also known as c.3939C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 3939. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This mutation has previously been reported in a Czech family with two cases of ovarian cancer (Pohlreich P et al. Breast Cancer Res. 2005 Jul;7:R728-36). In addition to the clinical data presented in the literature, his 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
Intensive Surveillance with Biannual Dynamic Contrast-Enhanced Magnetic Resonance Imaging Downstages Breast Cancer in BRCA1 Mutation Carriers.	Guindalini RSC	Clinical cancer research : an official journal of the American Association for Cancer Research	2019	PMID: 30154229
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.	Rebbeck TR	Human mutation	2018	PMID: 29446198
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
High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area.	Pohlreich P	Breast cancer research : BCR	2005	PMID: 16168118

Text-mined citations for rs80358641 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.3939C>G (p.Tyr1313Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80358641 ...