VCV000052847.25 - ClinVar

NM_000059.4(BRCA2):c.9477C>A (p.Phe3159Leu)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance (4); Likely benign (3)

7 out of 8 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value 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.9477C>A (p.Phe3159Leu)

Variation ID: 52847 Accession: VCV000052847.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32394909 (GRCh38) [ NCBI UCSC ] 13: 32969046 (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 15, 2026	Dec 22, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.9477C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Phe3159Leu	missense
NC_000013.11:g.32394909C>A
NC_000013.10:g.32969046C>A
NG_012772.3:g.84430C>A
LRG_293:g.84430C>A
LRG_293t1:c.9477C>A	LRG_293p1:p.Phe3159Leu
U43746.1:n.9705C>A

... more HGVS ... less HGVS

Protein change

F3159L

Other names

Canonical SPDI

NC_000013.11:32394908:C:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA026174 dbSNP: rs80359221 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	21902	22070

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 breast ovarian cancer syndrome	Uncertain significance (1)	criteria provided, single submitter	Dec 22, 2025	RCV000045831.14
Breast-ovarian cancer, familial, susceptibility to, 2	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	May 17, 2024	RCV000114116.5
Hereditary cancer-predisposing syndrome	Likely benign (2)	criteria provided, multiple submitters, no conflicts	May 16, 2025	RCV000221995.13
not provided	Uncertain significance (1)	criteria provided, single submitter	Apr 19, 2019	RCV000985628.2
not specified	Uncertain significance (1)	criteria provided, single submitter	May 8, 2025	RCV002281735.2

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.
Uncertain significance (Apr 19, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria)	not provided	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001133983.3 First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022	Publications: PubMed (2) PubMed: 19043619‚ 27062684 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Dec 22, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hereditary breast ovarian cancer syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000073844.13 First in ClinVar: Jul 03, 2013 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 27062684‚ 28492532‚ 34178674‚ 37922907 Comment: show This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3159 of the BRCA2 protein (p.Phe3159Leu). This variant is present in population databases (rs80359221, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27062684, 34178674). ClinVar contains an entry for this variant (Variation ID: 52847). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 37922907). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (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

Likely benign (Jun 08, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Color Diagnostics, LLC DBA Color Health Accession: SCV000906963.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Likely Benign (Feb 15, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV004846182.1 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)	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1 Zygosity: 1 Single Heterozygote

Uncertain significance (May 08, 2025) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002571893.2 First in ClinVar: Sep 17, 2022 Last updated: Jun 22, 2025	Publications: PubMed (4) PubMed: 19043619‚ 27062684‚ 34178674‚ 37922907 Comment: show Variant summary: BRCA2 c.9477C>A (p.Phe3159Leu) results in a non-conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 4e-06 in 251178 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9477C>A has been reported in the literature in the presumed heterozygous state in individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (Azzollini_2016, Fanale_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function in vitro. These results showed no damaging effect of this variant (example, Biswas_2023). The following publications have been ascertained in the context of this evaluation (PMID: 27062684, 34178674, 19043619, 37922907). ClinVar contains an entry for this variant (Variation ID: 52847). Based on the evidence outlined above, the variant was classified as uncertain significance. (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

Likely benign (May 16, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV000276099.9 First in ClinVar: May 29, 2016 Last updated: Jul 13, 2025	Publications: PubMed (2) PubMed: 19043619‚ 27062684 Comment: show This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (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

Uncertain significance (May 17, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance)	Molecular Pathology, Peter Maccallum Cancer Centre Accession: SCV006277423.1 First in ClinVar: Jul 13, 2025 Last updated: Jul 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Dec 23, 2003) N Not contributing to aggregate classification	no assertion criteria provided	Breast-ovarian cancer, familial 2	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000147647.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Observation: 2 Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Observation 2 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Ethnicity/Population group: Central/Eastern European

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3159 of the BRCA2 protein (p.Phe3159Leu). This variant is present in population databases (rs80359221, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27062684, 34178674). ClinVar contains an entry for this variant (Variation ID: 52847). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 37922907). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Variant summary: BRCA2 c.9477C>A (p.Phe3159Leu) results in a non-conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 4e-06 in 251178 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9477C>A has been reported in the literature in the presumed heterozygous state in individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (Azzollini_2016, Fanale_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function in vitro. These results showed no damaging effect of this variant (example, Biswas_2023). The following publications have been ascertained in the context of this evaluation (PMID: 27062684, 34178674, 19043619, 37922907). ClinVar contains an entry for this variant (Variation ID: 52847). Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Sequencing-based functional assays for classification of BRCA2 variants in mouse ESCs.	Biswas K	Cell reports methods	2023	PMID: 37922907
Prevalence and Spectrum of Germline BRCA1 and BRCA2 Variants of Uncertain Significance in Breast/Ovarian Cancer: Mysterious Signals From the Genome.	Fanale D	Frontiers in oncology	2021	PMID: 34178674
Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study.	Azzollini J	European journal of internal medicine	2016	PMID: 27062684
Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios.	Karchin R	Cancer informatics	2008	PMID: 19043619
The breast cancer information core: database design, structure, and scope.	Szabo C	Human mutation	2000	PMID: 10923033

Text-mined citations for rs80359221 ...

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 13, 2026