Variant chr13-32336694-C-G details in Genebe, Genetics Data Aggregator

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 links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 id is 141070.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32336694-C-G is described in Lovd as [Pathogenic]. Variant chr13-32336694-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.2339C>G	p.Ser780Ter	stop_gained	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.2339C>G	p.Ser780Ter	stop_gained	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250872

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135674

show subpopulations

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 SAS exome

AF:

0.00

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:

AN:

1461552

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 21, 2017	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 28, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	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). -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 29, 2021	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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Oct 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 17, 2023	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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 29, 2015	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2019	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. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.2426T>G, p.Leu809X; c.2517C>A, p.Tyr839X; c.2830A>T, p.Lys944X). The variant allele was found at a frequency of 4.1e-06 in 245776 control chromosomes (gnomAD). The variant, c.2339C>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Konstantopoulou_2014, Couch_2016, Kwong_2016, Chao_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 16, 2021	- -
Pathogenic, no assertion criteria provided	literature only	Center for Precision Medicine, Meizhou People's Hospital	-	- -

Malignant tumor of breast

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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 â€šÃ„Ãºwith pathogenic alleleâ€šÃ„Ã¹, 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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.32

Eigen_PC

Benign

-0.013

FATHMM_MKL

Benign

0.13

MutationTaster

Benign

1.0

A;A

Vest4

0.93

GERP RS

2.5

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

chr13-32336694-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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