13-32340037-C-G

Variant names:

• chr13-32340037-C-G
• rs41293497
• NM_000059.4:c.5682C>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.5682C>G​(p.Tyr1894*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,256 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. Y1894Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:46
• Conservation: PhyloP100: 0.349
• Publications: 76 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32340037-C-G is Pathogenic according to our data. Variant chr13-32340037-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 37989.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.5682C>G	p.Tyr1894*	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.5682C>G	p.Tyr1894*	stop_gained	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5313C>G	p.Tyr1771*	stop_gained	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5682C>G		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250362 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461212 Hom.: 0 Cov.: 44 AF XY: 0.0000316 AC XY: 23 AN XY: 726904

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53202

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

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111768

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74242

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:46

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:17

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

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 19, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 02, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 07, 2021

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM5_PTC_Strong -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 22, 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. -

Jan 28, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2015

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. -

Dec 13, 2023

All of Us Research Program, National Institutes of 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 18 individuals affected with breast and/or ovarian cancer (PMID: 11179017, 16168118, 18042939, 17972171, 20104584, 25682074, 25927356, 26219728, 26687385, 27741520, 28294317, 28724667, 28831036, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001092): and in individuals affected with pancreatic, prostate and colorectal cancer (PMID: 20736950, 29360161, 29478780). This variant also has been reported in related individuals affected with Fanconi anemia (PMID: 15070707). This variant has been identified in 1/250362 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. -

not provided Pathogenic:7

Feb 22, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Identified in individuals with a personal or family history consistent with pathogenic variants in this gene (Risch et al., 2001; Pohlreich et al., 2005; Edwards et al., 2010; Cini et al., 2016; Fernandes et al., 2016; Kim et al., 2016; Dudley et al., 2018); 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; Also known as 5910C>G; This variant is associated with the following publications: (PMID: 20736950, 29446198, 29339979, 29360161, 32211327, 29922827, 28888541, 24055113, 25525159, 11897832, 11179017, 27003155, 24156927, 26852015, 25637381, 26852130, 26219728, 25682074, 26848529, 27225637, 27741520, 27836010, 28176296, 28294317, 27356891, 28724667, 28423363, 29478780, 29907814, 29909963, 16168118, 29161300, 30720243, 19471317, 17972171, 18042939, 15340362, 15070707, 31174498, 31528241, 20104584, 30702160, 32467295, 34399810, 11597388, 32318955, 32521533, 31447099, 32101877, 31825140, 32885271, 30787465, 33087929, 33804961) -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Tyr1894* variant was identified in 18 of 8970 proband chromosomes (frequency: 0.002) from Chinese, Italian, and Czech individuals or families with breast, ovarian and prostate cancers and was not identified in 182 control chromosomes from healthy individuals (Cini 2016, Cao WM, Risch 2001, Edwards 2010, Pohlreich 2005, Borg 2010, Caux-Moncoutier 2009). The variant was also identified in dbSNP (ID: rs41293497) as “With Likely benign, Pathogenic allele”, and in the NHLBI GO Exome Sequencing Project in 1 of 8596 European American alleles (frequency: 0.0001). The variant was identified in ClinVar (classified as pathogenic by ENIGMA, GeneDX, Invitae, Ambry Genetics, and five other submitters). In addition, the variant was identified as pathogenic in the COGR database by Women’s College Hospital, Children’s’ Hospital of Eastern Ontario, Kingston General Hospital – Queen’s University and North York General Hospital. The variant was also identified by our laboratory in three individuals with breast and basal cell carcinomas, in the BIC database (67x as Class 5 with clinical importance), and in the ARUP Laboratories BRCA Mutations Database (as definitely pathogenic). The variant was not identified in COSMIC, the Fanconi Anemia Mutation Database (LOVD), the 1000 Genomes Project, or the Exome Aggregation Consortium database (August 8, 2016). The p.Tyr1894* variant leads to a premature stop codon at position 1894, 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 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. -

Apr 13, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/250362 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with breast cancer (PMID: 18042939 (2007), 28724667 (2017), 29907814 (2018), 31174498 (2019), 32029870 (2020)), ovarian cancer (PMID: 1179017 (2001)), prostate cancer (PMID: 20736950 (2010)), gastric cancer (PMID: 32521533 (2020)), and liver cancer (PMID: 34399810 (2021)). Based on the available information, this variant is classified as pathogenic. -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PVS1, PM2 -

Aug 08, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3, PM5_strong, PVS1 -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:7

Jun 14, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA2 c.5682C>G (p.Tyr1894X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.6644_6647delACTC, c.6682dupG, c.6997_6998delGT, etc.). This variant is absent in 120576 control chromosomes from ExAC. This variant is a recurrent pathogenic mutation found in several HBOC patients/families and in individuals undergoing BRCA1/2 clinical testing. In compound heterozygous with another variant, it has also been reported to cause Fanconi Anemia. Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as a Disease Variant (or Pathogenic). -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

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.Tyr1894*) 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 (rs41293497, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer, breast cancer, prostate cancer, and Fanconi anemia (PMID: 11179017, 15070707, 16168118, 18042939, 20736950). This variant is also known as 5910C>G. ClinVar contains an entry for this variant (Variation ID: 37989). For these reasons, this variant has been classified as Pathogenic. -

Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 13, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5682C>G (p.Tyr1894*) variant in the BRCA2 gene is located on the exon 11 and is predicted to introduce a premature translation termination codon (p.Tyr1894*), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832). This variant has been reported in more than 10 unrelated individuals with breast or ovarian cancer (PMID: 35912179, 31528241, 26852015, 31837001, 33113089, 36119527). This variant is reported in ClinVar as pathogenic (ID: 37989) and reviewed by the expert panel. This variant is rare in the general population according to gnomAD (1/250362). Therefore, the c.5682C>G (p.Tyr1894*) variant of BRCA2 has been classified as pathogenic. -

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr1894X (c.5682C>G) variant in BRCA2 has been reported in >20 individuals with BRCA2-related cancers (Risch 2001, Edwards 2010, Tea 2014, Alemar 2017, AlDubayan 2018, Dudley 2018, BIC database). Furthermore, another variant at this position resulting in the same amino acid change (c.5681dup, p.Tyr1894X) is classified as pathogenic for hereditary breast and ovarian cancer (HBOC) by our laboratory. The c.5682C>G variant has also been identified in 0.001% (1/113148) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of HBOC in the general population. This nonsense variant is predicted to lead to a premature termination codon at position 1894, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in HBOC. Finally, the p.Tyr1894X (c.5682C>G) variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37989). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4, PS1. -

Hereditary cancer-predisposing syndrome Pathogenic:4

Feb 15, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y1894* pathogenic mutation (also known as c.5682C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 5682. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) cohorts (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Marroni F et al. Eur J Hum Genet, 2004 Nov;12:899-906; Pohlreich P et al. Breast Cancer Res. 2005 Jul;7:R728-36; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Tea MK et al. Maturitas, 2014 Jan;77:68-72; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Lang GT et al. Int. J. Cancer 2017 Jul;141(1):129-142; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Alemar B et al. PLoS One, 2017 Nov;12:e0187630; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Wu H et al. Hum Hered, 2019 Feb;84:160-169; Cao WM et al. BMC Cancer, 2019 Jun;19:551; Guo X et al. Int J Cancer, 2020 04;146:2175-2181; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473; Meng H et al. Int J Cancer, 2020 06;146:3044-3052; Liu Y et al. J Hematol Oncol, 2021 01;14:18; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879), including patients with male breast cancer (Tai YC et al. J Natl Cancer Inst, 2007 Dec;99:1811-4). This mutation has also been reported in individuals with prostate, pancreatic, colorectal and gastric cancers (Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; AlDubayan SH et al. Am J Hum Genet, 2018 03;102:401-414; Dudley B et al. Cancer, 2018 04;124:1691-1700; Wei Y et al. Oncologist, 2020 07;25:e1042-e1050; Zhou J et al. Oncology, 2020 Jun;98:583-588), as well as in members of one Fanconi anemia family (Wagner JE et al. Blood, 2004 Apr;103:3226-9). 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. -

Jan 26, 2018

Academic Department of Medical Genetics, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -

Mar 14, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 13, 2024

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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 18 individuals affected with breast and/or ovarian cancer (PMID: 11179017, 16168118, 18042939, 17972171, 20104584, 25682074, 25927356, 26219728, 26687385, 27741520, 28294317, 28724667, 28831036, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001092): and in individuals affected with pancreatic, prostate and colorectal cancer (PMID: 20736950, 29360161, 29478780). This variant also has been reported in related individuals affected with Fanconi anemia (PMID: 15070707). This variant has been identified in 1/250362 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. -

Breast and/or ovarian cancer Pathogenic:2

Nov 23, 2015

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:2

-

Center for Precision Medicine, Meizhou People's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 01, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;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

Oct 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Jan 15, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM5_STR -

Inherited breast cancer and ovarian cancer Pathogenic:1

Apr 09, 2025

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ovarian cancer Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Medulloblastoma;C0040588:Esophageal atresia/tracheoesophageal fistula;C0346153:Familial cancer of breast;C0376358:Prostate cancer;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

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Pathogenic:1

Jun 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.5682C>G variant is predicted to result in premature protein termination (p.Tyr1894*). This variant has been documented to be causative for multiple cancers including breast, ovarian and prostate (see for example - Risch et al. 2001. PubMed ID: 11179017; Edwards et al. 2010. PubMed ID: 20736950; Dudley et al. 2018. PubMed ID: 29360161). In at least one individual this variant was reported in the compound heterozygous state in an individual with Fanconi anemia (Wagner et al. 2004. PubMed ID: 15070707). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted in ClinVar as pathogenic by multiple submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/37989/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Ovarian neoplasm Pathogenic:1

Dec 01, 2018

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	33
DANN	Benign	0.95
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.061	N
PhyloP100		0.35
Vest4		0.89
GERP RS		-3.9
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: rs41293497; hg19: chr13-32914174;