NM_000059.4:c.2339C>G

Variant names:

• chr13-32336694-C-G
• rs587781471
• NM_000059.4:c.2339C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.2339C>G​(p.Ser780*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,552 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 0.0500
• Publications: 16 publications found

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32336694-C-G is Pathogenic according to our data. Variant chr13-32336694-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 141070.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.2339C>G	p.Ser780*	stop_gained	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.2339C>G	p.Ser780*	stop_gained	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.1970C>G	p.Ser657*	stop_gained	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.2339C>G		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250872 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461552 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727086

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111802

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein.

Feb 21, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

not provided Pathogenic:3

Jun 28, 2021

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.2339C>G, which results in the creation of a premature stop codon at amino acid position 780, p.Ser780*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA2 protein with potentially abnormal function. This pathogenic sequence change has previously been described in individuals with pancreatic cancer, male breast cancer, and individuals with a personal and/or family history of breast and ovarian cancer (PMID: 24010542, 29335925, 27157322, 29446198, 30702160, 25452441). The p.Ser880* pathogenic sequence change is present in the heterozygous state in a single individual in the gnomAD population database (dbSNP rs587781471). This variant has been classified as pathogenic by the expert panel for BRCA1/2 variants in ClinVar.

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is a substitution of one nucleotide base resulting in a single amino acid change from Serine to a termination codon at amino acid residue 780 of the BRCA2 gene. It results in a truncated non-functional protein. This variant has been reported in the international literature in patients with breast and/or ovarian cancer (PMID: 24010542, 27157322). The mutation database ClinVar contains entries for this variant (Variation ID: 141070).

Sep 09, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA2 c.2339C>G at the cDNA level and p.Ser780Ter (S780X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 c.2567C>G. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with breast and/or ovarian cancer (Konstantopoulou 2014, Kwong 2016, Couch 2015) and is considered pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:3

Feb 26, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S780* pathogenic mutation (also known as c.2339C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 2339. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been identified in multiple individuals and families with hereditary breast and ovarian cancer (HBOC) syndrome (Konstantopoulou I et al. Clin Genet, 2014 Jan;85:36-42; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Chao A et al. Oncotarget, 2016 Dec;7:85529-85541; Kotoula V et al. Am J Cancer Res, 2017 Jan;7:98-114; Apessos A et al. Cancer Genet, 2018 01;220:1-12; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Dorling et al. N Engl J Med. 2021 02;384:428-439), including a male patient with a personal history of breast and pancreatic cancer and a female patient with renal and uterine cancer (Fostira F et al. Breast Cancer Res Treat, 2018 May;169:105-113; Hartman TR et al. Sci Rep, 2020 08;10:13518). 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.

Oct 22, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Jul 17, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in a male individual affected with breast cancer and pancreatic cancer (PMID: 24010542, 29335925), five individuals affected with breast or ovarian cancer (PMID: 25452441, 33471991; Leiden Open Variation Database DB-ID BRCA2_003899, 35918668) and at least three hereditary breast and ovarian cancer families (PMID: 27157322, 29446198, 30702160). This variant has been identified in 1/250872 chromosomes 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.

Hereditary breast ovarian cancer syndrome Pathogenic:3

Dec 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.2339C>G (p.Ser780X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250872 control chromosomes. c.2339C>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Konstantopoulou_2014, Couch_2016, Kwong_2016, Chao_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24010542, 25452441, 27157322, 27907908, 29335925, 29446198, 30702160). ClinVar contains an entry for this variant (Variation ID: 141070). Based on the evidence outlined above, the variant was classified as pathogenic.

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser780*) 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 present in population databases (rs587781471, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24010542, 27157322). ClinVar contains an entry for this variant (Variation ID: 141070). For these reasons, this variant has been classified as Pathogenic.

Jul 29, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser780X variant in BRCA2 has been reported in 2 individuals with breast ca ncer (1 male and 1 female; Konstantopoulou 2014, Couch 2015), and was absent fro m large population studies. This nonsense variant leads to a premature terminati on codon at position 780, which is predicted to lead to a truncated or absent pr otein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this vari ant meets our criteria to be classified as pathogenic for HBOC in an autosomal d ominant manner based upon predicted impact to the protein and absence in control s.

Familial cancer of breast Pathogenic:2

Dec 16, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Center for Precision Medicine, Meizhou People's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Malignant tumor of breast Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Ser780* variant was identified in 7 of 29,390 proband chromosomes (frequency: 0.0002) from individuals or families with hereditary breast and ovarian cancer (Konstantopoulou 2014, Couch 2015, Kwong 2016, Rebbeck 2018, Chao 2016). The variant was identified in dbSNP (rs587781471) as “with pathogenic allele”, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx, Counsyl and 4 other submitters), LOVD 3.0 (observed 9x) and UMD-LSDB (observed 1x). The variant was identified in control databases in 1 of 250,872 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 1 of 18,388 chromosomes (freq: 0.00005); it was not observed in the African, Latino, Ashkenazi Jewish, Finnish, European, Other and South Asian populations. The c.2339C>G variant leads to a premature stop codon at position 780, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.
Eigen	Uncertain	0.32
Eigen_PC	Benign	-0.013
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.0	.;.
MetaRNN	Benign	0.0	.;.
MutationAssessor	Benign	0.0	.;.
PhyloP100		0.050
PROVEAN	Benign	0.0	.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.
Sift4G	Pathogenic	0.0	.;.
Vest4		0.93
GERP RS		2.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587781471; hg19: chr13-32910831; COSMIC: COSV105932227;