13-32362509-T-C

Variant names:

• chr13-32362509-T-C
• rs9534262
• NM_000059.4:c.7806-14T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000059.4(BRCA2):​c.7806-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 1,608,568 control chromosomes in the GnomAD database, including 223,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22039 hom., cov: 32)
  • Exomes 𝑓: 0.52 (201271 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:30 O:1
• Conservation: PhyloP100: -1.41
• Publications: 70 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 13-32362509-T-C is Benign according to our data. Variant chr13-32362509-T-C is described in ClinVar as Benign. ClinVar VariationId is 126158.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7806-14T>C		intron_variant	Intron 16 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7806-14T>C		intron_variant	Intron 16 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7437-14T>C		intron_variant	Intron 16 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7806-6T>C		splice_region_variant, intron_variant	Intron 15 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81547 AN: 151850 Hom.: 22016 Cov.: 32

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.518

GnomAD2 exomes AF: 0.523 AC: 130837 AN: 250228 AF XY: 0.520

Gnomad AFR exome AF: 0.570

Gnomad AMR exome AF: 0.514

Gnomad ASJ exome AF: 0.471

Gnomad EAS exome AF: 0.558

Gnomad FIN exome AF: 0.576

Gnomad NFE exome AF: 0.517

Gnomad OTH exome AF: 0.512

GnomAD4 exome AF: 0.524 AC: 763705 AN: 1456600 Hom.: 201271 Cov.: 35 AF XY: 0.523 AC XY: 379264 AN XY: 724988

African (AFR) AF: 0.557 AC: 18552 AN: 33312

American (AMR) AF: 0.514 AC: 22952 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 12436 AN: 26110

East Asian (EAS) AF: 0.608 AC: 24117 AN: 39648

South Asian (SAS) AF: 0.489 AC: 42139 AN: 86110

European-Finnish (FIN) AF: 0.574 AC: 30677 AN: 53398

Middle Eastern (MID) AF: 0.409 AC: 2349 AN: 5744

European-Non Finnish (NFE) AF: 0.523 AC: 579167 AN: 1107380

Other (OTH) AF: 0.520 AC: 31316 AN: 60206

GnomAD4 genome AF: 0.537 AC: 81625 AN: 151968 Hom.: 22039 Cov.: 32 AF XY: 0.540 AC XY: 40088 AN XY: 74292

African (AFR) AF: 0.567 AC: 23480 AN: 41422

American (AMR) AF: 0.536 AC: 8191 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 1645 AN: 3472

East Asian (EAS) AF: 0.571 AC: 2960 AN: 5182

South Asian (SAS) AF: 0.480 AC: 2314 AN: 4822

European-Finnish (FIN) AF: 0.572 AC: 6025 AN: 10540

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.521 AC: 35407 AN: 67948

Other (OTH) AF: 0.516 AC: 1088 AN: 2108

Alfa AF: 0.518 Hom.: 44682

Bravo AF: 0.533

Asia WGS AF: 0.526 AC: 1830 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:30 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:9 Other:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2015

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.5507 (Asian), 0.5589 (African), 0.5409 (European), derived from 1000 genomes (2012-04-30).

Sep 21, 2015

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 02, 2014

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

High frequency in a 1kG or ESP population: 50.4 %. 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.

Breast Cancer Information Core (BIC) (BRCA2)

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:9

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 16, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 01, 2017

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:3

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Dec 05, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 11, 2019

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Hereditary breast ovarian cancer syndrome Benign:3

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 29, 2013

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Benign:2

Feb 23, 2017

Baylor Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast and/or ovarian cancer Benign:1

Apr 22, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia complementation group D1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.5
DANN	Benign	0.81
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9534262; hg19: chr13-32936646; COSMIC: COSV66447577;