rs80358785

chr13-32340000-C-Achr13-32340000-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):c.5645C>A(p.Ser1882Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S1882S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:41 U:1 O:1
• Conservation: PhyloP100: 1.79

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32340000-C-A is Pathogenic according to our data. Variant chr13-32340000-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 37984.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340000-C-A is described in Lovd as [Pathogenic]. Variant chr13-32340000-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5645C>A	p.Ser1882Ter	stop_gained	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5645C>A	p.Ser1882Ter	stop_gained	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249416 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 134860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460314 Hom.: 0 Cov.: 45 AF XY: 0.00000826 AC XY: 6 AN XY: 726310

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: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:41 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 10, 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 12 individuals affected with breast and/or ovarian cancer (PMID: 15024741, 15689453, 20104584, 22535016, 22666503, 26439132, 27257965, 28039656, 28724667, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_000141) and four individuals affected with prostate cancer (PMID: 27433846, 31214711). This variant also has been reported in two siblings who were compound heterozygous carriers with a second pathogenic BRCA2 variant and were both affected with Wilms tumor (PMID: 15689453). This variant has been identified in 4/249416 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Medical University Innsbruck	Feb 11, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 19, 2011	- -
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	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Feb 21, 2019	The c.5645C>A (p.Ser1882*) variant in the BRCA2 gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple families affected with Hereditary Breast and Ovarian Cancer (PMID 10550133, 22144684, 28324225) and has also been reported in individuals affected with triple negative breast cancer (PMID 22666503), ovarian cancer (PMID 26439132) or metastatic prostate cancer (PMID 27433846). This variant is extremely rare in general population. Therefore, this c.5645C>A (p.Ser1882*) variant in the BRCA2 gene is classified as pathogenic. -

not provided Pathogenic:8 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Jul 29, 2022	PVS1, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 07, 2021	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with breast or prostate cancer in the published literature (PMID: 33918338 (2020), 27433846 (2016) and 22666503 (2012)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25682074, 30287823, 30430080, 29339979, 29446198, 30093976, 31263054, 15689453, 10660329, 22144684, 22535016, 22666503, 21952622, 22009639, 26439132, 26221963, 26064523, 25863477, 25802882, 27225637, 25525159, 24916970, 24249303, 27533253, 27836010, 26733283, 27271530, 27767231, 15131399, 26848529, 27433846, 28283652, 28324225, 28259476, 29084914, 28724667, 28993434, 28715532, 29215753, 29659587, 29346284, 30274973, 30078507, 30720243, 30702160, 30322717, 27257965, 32467295, 11597388, 32318955, 31447099, 32853339, 32341426, 31825140, 32710294, 30875412, 33608381, 30787465, 31742824) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	BRCA2: PVS1, PM2, PS4:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 04, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 31, 2016	Variant summary: The BRCA2 c.5645C>A (p.Ser1882X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/120628 (1/40160, 0.0000249), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333 (0.0007503). In addition, it needs to be noted that these three occurrences need to be cautiously considered due to the fact that the ExAC cohort contains individuals that could harbor a BRCA2 phenotype. However, multiple affected individuals have been reported via publications, along with numerous reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 17, 2018	The p.Ser1882X variant in BRCA2 has been reported in >60 individuals with BRCA2- associated cancers and segregated with disease in 2 affected relatives from 2 fa milies (Caputo 2012, De Silva 2017, Heidemann2012, Rebbeck 2016, Reid 2005). Thi s variant has also been identified in 1/17202 East Asian and 2/110946 European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs80358785). This nonsense variant leads to a premature terminati on codon at position 1882, which is predicted to lead to a truncated or absent p rotein. Heterozygous loss of function of the BRCA2 gene is an established diseas e mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this va riant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENI GMA expert panel (ClinVar SCV000282410.1). In summary, this variant meets criter ia to be classified as pathogenic for HBOC in an autosomal dominant manner based upon predicted impact to the protein, absence in the general population and pre sence in multiple affected individuals. ACMG/AMP Criteria applied: PVS1; PS4; PM 2 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Ser1882*) 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 (rs80358785, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast, ovarian and prostate cancer (PMID: 15024741, 21952622, 22144684, 22535016, 22666503). This variant is also known as 5873C>A. ClinVar contains an entry for this variant (Variation ID: 37984). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Research Institute, Aichi Cancer Center	Feb 01, 2022	- -

Breast and/or ovarian cancer Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Feb 13, 2004	- -
Pathogenic, no assertion criteria provided	case-control;clinical testing	CZECANCA consortium	Jun 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 17, 2017	- -

Familial cancer of breast Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Pathogenic, no assertion criteria provided	literature only	Center for Precision Medicine, Meizhou People's Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variant is a single amino acid change from Serine to a Termination codon at amino acid residue 1882 of the BRCA2 gene. It is expected to result in a truncated, non-functional protein. Truncating variants in the BRCA2 gene are known to be pathogenic. This variant is also known as 5873C>A in the literature and has been described in patients and families with breast, ovarian and prostate cancer (PMID: 22144684, 22535016, 22666503, 21952622, 15024741). The mutation database ClinVar contains entries for this variant (Variation ID: 37984). -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 16, 2024	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 reported in at least 12 individuals affected with breast and/or ovarian cancer (PMID: 15024741, 15689453, 20104584, 22535016, 22666503, 26439132, 27257965, 28039656, 28724667, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_000141) and four individuals affected with prostate cancer (PMID: 27433846, 31214711). This variant also has been reported in two siblings who were compound heterozygous carriers with a second pathogenic BRCA2 variant and were both affected with Wilms tumor (PMID: 15689453). This variant has been identified in 4/249416 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 28, 2022	The p.S1882* pathogenic mutation (also known as c.5645C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 5645. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been reported in an individual diagnosed with triple negative breast cancer at age 37 (Meyer P et al. PLoS One. 2012 May;7:e38361), in two individuals with ovarian cancer (Sakomoto I et al. Cancer. 2016 Jan;122:84-90), and in a family with multiple cases of breast cancer (Verhoog LC et al. J. Clin. Oncol. 1999 Nov;17:3396-402). In another study, this alteration was reported as an Eastern European founder mutation (Caputo S et al. Nucleic Acids Res. 2012 Jan;40:D992-1002). This mutation has also been detected in a cohort of affected patients meeting genetic testing criteria for HBOC (Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238), a cohort of patients with metastatic prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53), as well as in multiple cohorts of unselected breast cancer patients (Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Zhong X et al. PLoS ONE. 2016 Jun;11:e0156789). In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in 7 members of one family (Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3). 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	Dec 20, 2021	- -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 08, 2022

- -

Malignant tumor of prostate;C4763838:Metastatic Prostate Small Cell Carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Rudy L. Ruggles Biomedical Research Institute, Danbury Hospital

Apr 15, 2020

This BRCA2 variant (rs80358785) has been found in 65 year-old man with a germline BRCA2 mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer. -

Breast neoplasm Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Nov 01, 2015

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Breast carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Dec 10, 2021

_x000D_ Criteria applied: PVS1, PS4, PM2_SUP -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 26, 2019

The BRCA2 c.5645C>A; p.Ser1882Ter variant (rs80358785), also known as 5873C>A, is reported in several individuals with hereditary breast and ovarian cancer syndrome and is described as a founder mutation in the Eastern European population (Caputo 2012, Heramb 2018, Meisel 2017, Momozawa 2018). It has also been reported in two brothers with Wilms tumor and brain tumors, who also carry an additional truncating variant in trans (Reid 2005). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37984). It is found in the general population with a low overall allele frequency of 0.002% (4/249416 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Caputo S et al. Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res. 2012 Jan;40(Database issue):D992-1002. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. Meisel C et al. Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study. Arch Gynecol Obstet. 2017 May;295(5):1227-1238. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. Reid S et al. Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. J Med Genet. 2005 Feb;42(2):147-51. -

Neoplasm of ovary Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

BRCA2-Related Disorders Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 05-19-2017 by Lab Myriad Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.059
FATHMM_MKL	Benign	0.35	N
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		5.7

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

Other links and lift over

dbSNP: rs80358785; hg19: chr13-32914137; COSMIC: COSV66450717;