13-32394673-T-C

Variant names:

• chr13-32394673-T-C
• rs11571818
• NM_000059.4:c.9257-16T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000059.4(BRCA2):​c.9257-16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00788 in 1,609,366 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (69 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:26
• Conservation: PhyloP100: 0.00
• Publications: 21 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=-0.84).
• BP6: Variant 13-32394673-T-C is Benign according to our data. Variant chr13-32394673-T-C is described in ClinVar as Benign. ClinVar VariationId is 52790.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00601 (915/152358) while in subpopulation NFE AF = 0.0085 (578/68034). AF 95% confidence interval is 0.00792. There are 3 homozygotes in GnomAd4. There are 437 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.9257-16T>C		intron	N/A	NP_000050.3
	BRCA2	NM_001432077.1		c.9257-16T>C		intron	N/A	NP_001419006.1
	BRCA2	NM_001406720.1		c.9206-16T>C		intron	N/A	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.9257-16T>C		intron	N/A	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.9257-16T>C		intron	N/A	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.8888-16T>C		intron	N/A	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.00602 AC: 916 AN: 152240 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00849

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00659 AC: 1610 AN: 244488 AF XY: 0.00687

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00265

Gnomad ASJ exome AF: 0.00403

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.00901

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00807 AC: 11761 AN: 1457008 Hom.: 69 Cov.: 31 AF XY: 0.00823 AC XY: 5961 AN XY: 724638

African (AFR) AF: 0.00120 AC: 40 AN: 33390

American (AMR) AF: 0.00265 AC: 118 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00449 AC: 117 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00647 AC: 554 AN: 85614

European-Finnish (FIN) AF: 0.00974 AC: 517 AN: 53068

Middle Eastern (MID) AF: 0.00719 AC: 39 AN: 5422

European-Non Finnish (NFE) AF: 0.00896 AC: 9941 AN: 1109130

Other (OTH) AF: 0.00723 AC: 435 AN: 60156

GnomAD4 genome AF: 0.00601 AC: 915 AN: 152358 Hom.: 3 Cov.: 33 AF XY: 0.00587 AC XY: 437 AN XY: 74506

African (AFR) AF: 0.00118 AC: 49 AN: 41582

American (AMR) AF: 0.00510 AC: 78 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4828

European-Finnish (FIN) AF: 0.0104 AC: 111 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00850 AC: 578 AN: 68034

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00737 Hom.: 3

Bravo AF: 0.00539

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:26

Revision: reviewed by expert panel

Submissions by phenotype

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 22, 2016

Fulgent Genetics, Fulgent Genetics

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 15, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 10, 2014

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

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.

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 0.01055 (European), derived from 1000 genomes (2012-04-30).

not specified Benign:7

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 13, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.9257-16T>C variant was identified in 121 of 53524 proband chromosomes (frequency: 0.002) from individuals or families with Breast and Ovarian cancer, and was present in 4 of 530 control chromosomes (frequency: 0.08) from healthy individuals (Caputo 2011, Borg 2010, Hadijisavvas 2003, Cvok 2008, Diez 2003). The variant was identified in dbSNP (ID: rs11571818) with “other” allele, with a minor allele frequency of 0.0044(1000 Genomes Project); in NHLBI Exome Sequencing Project (Exome Variant Server) in 67 of 8600 European and 10 of 4406 African Americans; in Exome Aggregation Consortium (ExAC) database in 574(3 homozygote) of 56204 of Europeans(non-Finnish), in 15 of 9522 Africans, in 25 of 10298 Latinos, in 116 (4 homozygote) of 15288 South Asians , in 77 (2 homozygote) of 6222 Europeans (Finnish) and 5 of 820 other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also found in LOVD, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports, classified as benign by Invitae, as benign by Counsyl, as benign by GeneDX, as benign by Emory Genetics, as Likely benign by CHEO and as uncertain significance by BIC). It was also identified in GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (1X, classified as “likely benign” by a clinical laboratory), the BIC database (12X with no clinical importance), and UMD (73X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1:c.5116G>A (p.Gly1706Arg), c.4391delC (p.Pro1464LeufsX2), c.81_134delp.Cys27X); BRCA2:c.6275_6276delTT (p.Leu2092ProfsX7), c.4889C>G (p.Ser1630X), increasing the likelihood that the c.9257-16T>C variant does not have clinical significance. The c.9257-16T>C variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition splicing studies (Bonnet 2008, Claes 2003) showed that the c.9257-16T>C do not result in aberrant splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2014

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Benign:2

Nov 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:2

Dec 09, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 15, 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.

Familial cancer of breast Benign:2

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 23, 2017

Baylor Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast and/or ovarian cancer Benign:1

Apr 28, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.32
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs11571818; hg19: chr13-32968810; COSMIC: COSV104701316;