13-32356550-C-T

Variant names:

• chr13-32356550-C-T
• rs80358981
• NM_000059.4:c.7558C>T

Variant summary

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

The NM_000059.4(BRCA2):​c.7558C>T​(p.Arg2520*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,094 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:36
• Conservation: PhyloP100: 3.42

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 13-32356550-C-T is Pathogenic according to our data. Variant chr13-32356550-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 52353.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32356550-C-T is described in Lovd as [Pathogenic]. Variant chr13-32356550-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7558C>T	p.Arg2520*	stop_gained	Exon 15 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7558C>T	p.Arg2520*	stop_gained	Exon 15 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7189C>T	p.Arg2397*	stop_gained	Exon 15 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7558C>T		non_coding_transcript_exon_variant	Exon 14 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251188 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000180 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:36

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:11

Oct 17, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Oct 04, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.7558C>T (p.Arg2520*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in multiple individuals with breast and/or ovarian cancer (PMIDs: 36853301 (2023), 36171877 (2022), 35834759 (2022), 28194609 (2017), 25863477 (2015), 22009639 (2012), 21913181 (2012), 21990299 (2011), 14981104 (2004), 9150154 (1997)). This variant has also been reported in individuals with prostate cancer (PMID: 29433453 (2018)), pancreatic cancer (PMID: 24959366 (2014)) and biliary tract cancer (PMID: 29360550 (2018)). The frequency of this variant in the general population, 0.000026 (3/113554 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Apr 30, 2024

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified by standard clinical testing. female patient with triple negativ breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1 -

Nov 14, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PP5 -

Jan 09, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.7558C>T; p.Arg2520Ter variant (rs80358981) has been described in individuals with breast, ovarian, pancreatic, prostate and testicular cancer (Hakansson 1997, Yang 2011, Schultheis 2014). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 52353) and observed in the general population at a low overall frequency of 0.0016% (4/245940 alleles) in the Genome Aggregation Database. This variant introduces a premature termination codon, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Hakansson S et al. Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer. Am J Hum Genet. 1997;60(5):1068-78. Schultheis A et al. Squamous Cell Carcinoma of the Pancreas in a Patient with Germline BRCA2 Mutation-Response to Neoadjuvant Radiochemotherapy. Case Rep Oncol Med. 2014;2014:860532. Yang D et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011;306(14):1557-65. -

Feb 20, 2020

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; Observed in individuals with a personal and family history consistent with pathogenic variants in this gene (Hakansson 1997, Malander 2004, Pal 2005, Yang 2011, Bayraktar 2012, Schultheis 2014, Nakamura 2015, Wong-Brown 2015, Kwong 2016); 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: 25525159, 25863477, 26315209, 26296701, 27067391, 28188963, 28008555, 29339979, 9150154, 24959366, 24249303, 21990299, 21913181, 20104584, 14981104, 14746861, 25682074, 27157322, 22009639, 25637381, 25985138, 25085752, 16284991, 28194609, 29433453, 28831036, 27989354, 28724667, 30050867, 29360550, 28993434, 30720863, 29446198, 30720243, 30706003, 30702160, 30322717, 32846166, 33646313, 31447099, 32853339, 31825140, 32719484, 32338768, 30787465, 33087929) -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PVS1, PM2, PS4:Moderate -

Sep 14, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:10

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 14, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 16, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

-

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. -

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 14, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.7558C>T (p.Arg2520*) variant in exon 15 of the BRCA2 gene creates a premature translation termination codon and is predicted to result in loss of function through nonsense-mediated mRNA decay or by producing a truncated protein, which is a known disease mechanism for this gene. This variant has been reported in multiple hereditary breast and ovarian cancer patients (PMID: 9150154, 21990299, 22009639, 24959366, 25863477, 16284991, 25525159) and an individual with pancreatic cancer (PMID: 24959366). The c.7558C>T (p.Arg2520*) variant in the BRCA2 gene is classified as pathogenic. -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

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

- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Sep 15, 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.7558C>T (p.Arg2520X) 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. If a protein product is made, it is predicted to truncate the helical domain, nucleic acid-binding/OB-fold domain, tower domain, and oligonucleotide/oligosaccharide-binding 1 domain (via InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.7721G>A/p.Trp2574X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/120748 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in many HBOC patients in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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

- -

Feb 02, 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.Arg2520*) 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 (rs80358981, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and pancreatic cancer (PMID: 9150154, 14981104, 16284991, 20104584, 21990299, 22009639, 23242139, 24959366, 25863477). This variant is also known as 7786C>T. ClinVar contains an entry for this variant (Variation ID: 52353). For these reasons, this variant has been classified as Pathogenic. -

Apr 24, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg2520X variant in BRCA2 has been reported in >40 individuals with BRCA2-associated cancers (Hàkansson 1997, Bayraktar 2012, Castéra 2014, Schultheis 2014, Breast Cancer Information Core (BIC) database), and segregated with associated cancers in 2 affected relatives from 1 family. This variant has also been identified in 3/113554 European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population This nonsense variant leads to a premature termination codon at position 2520, which is predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based on the low frequency in controls, presence in affected individuals, and predicted impact to the protein. ACMG/AMP Criteria applied: PVS1, PS4, PM2_Supporting. -

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

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Oct 09, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R2520* pathogenic mutation (also known as c.7558C>T), located in coding exon 14 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7558. This changes the amino acid from an arginine to a stop codon within coding exon 14. This mutation has been reported in multiple Hereditary Breast and Ovarian Cancer Syndrome (HBOC) families from various ethnic backgrounds (Håkansson S et al. Am J Hum Genet, 1997 May;60:1068-78; Adem C et al. Cancer, 2003 Jan;97:1-11; Malander S et al. Eur J Cancer, 2004 Feb;40:422-8; Rebbeck TR et al. J Clin Oncol, 2004 Mar;22:1055-62; Pal T et al. Cancer, 2005 Dec;104:2807-16; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Yang D et al. JAMA, 2011 Oct;306:1557-65; Litton JK et al. Cancer, 2012 Jan;118:321-5; Bayraktar S et al. Cancer, 2012 Mar;118:1515-22; Haiman CA et al. PLoS Genet, 2013 Mar;9:e1003419; Castéra L et al. Eur J Hum Genet, 2014 Nov;22:1305-13; Wong-Brown MW et al. Breast Cancer Res Treat, 2015 Feb;150:71-80; Kang E et al. Breast Cancer Res Treat, 2015 May;151:157-68; Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Shirts BH et al. Genet Med, 2016 10;18:974-81; Donenberg T et al. Breast Cancer Res Treat, 2016 08;159:131-8; Maxwell KN et al. Nat Commun, 2017 08;8:319; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Zidekova D et al. Neoplasma;65:309-315; Arai M et al. J Hum Genet, 2018 Apr;63:447-457; Wardell CP et al. J. Hepatol., 2018 05;68:959-969; Wen WX et al. J Med Genet, 2018 02;55:97-103; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Kwong A et al. Oncotarget, 2018 Jan;9:7832-7843; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; Manchana T et al. World J Clin Oncol, 2019 Nov;10:358-368). In one study, this variant was reported in 10/60,466 breast cancer cases as well as in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in patients with prostate, pancreatic, esophageal and renal cancers (Na R et al. Eur Urol, 2017 05;71:740-747; Ibrahim M et al. BMC Cancer, 2018 02;18:179; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149; Wu Y et al. Eur Urol Oncol, 2020 04;3:224-230; Veyseh M et al. Front Oncol, 2018 Jul;8:259; Toss A et al. Cancers (Basel), 2019 Feb;11; Wolfe AR et al. Adv Radiat Oncol Sep;4:10-14; Ko JM et al. Int J Cancer, 2020 02;146:1042-1051; Hartman TR et al. Sci Rep, 2020 08;10:13518). This alteration has also been detected in cohorts of healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239; Qin Z et al. J Med Genet, 2021 Sep;58:587-591). Of note, this alteration is also designated as 7786C>T in published literature. 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. -

Apr 05, 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 15 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 detected in over 30 individuals and families affected with breast and ovarian cancer (PMID: 9150154, 14746861, 15131399, 16284991, 20104584. 21990299, 21913181, 25682074, 25863477, 26295337, 28724667, 28993434, 30287823, 33471991) and 4 unaffected carriers (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001041). This variant has been identified in 5/251188 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. -

Sep 19, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Familial cancer of breast Pathogenic:2

Mar 14, 2024

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

- -

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

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Pathogenic:1

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

- -

BRCA2-related cancer predisposition Pathogenic:1

Sep 16, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7558C>T variant in the BRCA2 gene is located on exon 15 and introduces a premature translation termination codon (p.Arg2520*), resulting in an absent or disrupted protein product. The variant has been reported in multiple unrelated individuals with breast/ovarian/prostate cancer (PMID: 34570441, 29534594, 28194609, 35834759, 36853301, 31467961, 36171877). Other frameshift/truncating variants in the same exon have been reviewed as pathogenic (p.Ala2513fs, p.Ala2526fs, ClinVar ID: 52350, 225751). Loss-of-function variants in the BRCA2 gene are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 52353) and reviewed by the expert panel. The variant is rare in general population according to gnomAD (5/251188 chromosomes). Therefore, the c.7558C>T (p.Arg2520*) variant in the BRCA2 gene has been classified as pathogenic. -

Breast neoplasm Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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 p.Arg2520X variant is identified in 2 out of 4418 proband chromosomes with unilateral and familial breast cancers, although it was not investigated in controls (Håkansson 1997, Borg 2010). It was listed in the dbSNP database as coming from a "clinical source" (ID#: rs80358981) with no frequency information available. However, this variant has been presented as a clinically important variant in the UMD (3 times) and the BIC (44 times) databases. The p.Arg2520X variant leads to a premature stop codon at position 2520, which is predicted to lead to a truncated or absent BRCA2 protein. Loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.83	D
Vest4		0.93
GERP RS		1.9

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: rs80358981; hg19: chr13-32930687; COSMIC: COSV66450365;