rs766173

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000059.4(BRCA2):c.865A>C(p.Asn289His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0418 in 1,598,150 control chromosomes in the GnomAD database, including 2,166 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N289S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.041 ( 218 hom., cov: 32)

Exomes 𝑓: 0.042 ( 1948 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:38O:1

Conservation

PhyloP100: 0.498

Publications

151 publications found

Variant links:

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

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015439987).

BP6

Variant 13-32332343-A-C is Benign according to our data. Variant chr13-32332343-A-C is described in ClinVar as Benign. ClinVar VariationId is 41567.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.865A>C	p.Asn289His	missense_variant	Exon 10 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.865A>C	p.Asn289His	missense_variant	Exon 10 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.496A>C	p.Asn166His	missense_variant	Exon 10 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.865A>C		non_coding_transcript_exon_variant	Exon 9 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0409

AC:

6221

AN:

152198

Hom.:

215

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0213

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0970

Gnomad ASJ

AF:

0.0441

Gnomad EAS

AF:

0.100

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.0148

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0344

Gnomad OTH

AF:

0.0463

GnomAD2 exomes

AF:

0.0521

AC:

12475

AN:

239502

AF XY:

0.0548

show subpopulations

Gnomad AFR exome

AF:

0.0222

Gnomad AMR exome

AF:

0.0731

Gnomad ASJ exome

AF:

0.0383

Gnomad EAS exome

AF:

0.103

Gnomad FIN exome

AF:

0.0154

Gnomad NFE exome

AF:

0.0350

Gnomad OTH exome

AF:

0.0495

GnomAD4 exome

AF:

0.0419

AC:

60573

AN:

1445834

Hom.:

1948

Cov.:

AF XY:

0.0445

AC XY:

31960

AN XY:

719010

show subpopulations

African (AFR)

AF:

0.0205

AC:

668

AN:

32626

American (AMR)

AF:

0.0752

AC:

3144

AN:

41798

Ashkenazi Jewish (ASJ)

AF:

0.0411

AC:

1056

AN:

25664

East Asian (EAS)

AF:

0.119

AC:

4709

AN:

39582

South Asian (SAS)

AF:

0.115

AC:

9497

AN:

82778

European-Finnish (FIN)

AF:

0.0151

AC:

805

AN:

53242

Middle Eastern (MID)

AF:

0.0560

AC:

318

AN:

5674

European-Non Finnish (NFE)

AF:

0.0341

AC:

37654

AN:

1104720

Other (OTH)

AF:

0.0456

AC:

2722

AN:

59750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2833

5666

8499

11332

14165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1536

3072

4608

6144

7680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0410

AC:

6240

AN:

152316

Hom.:

218

Cov.:

AF XY:

0.0436

AC XY:

3248

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0213

AC:

887

AN:

41570

American (AMR)

AF:

0.0978

AC:

1496

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0441

AC:

153

AN:

3468

East Asian (EAS)

AF:

0.100

AC:

520

AN:

5192

South Asian (SAS)

AF:

0.114

AC:

550

AN:

4820

European-Finnish (FIN)

AF:

0.0148

AC:

157

AN:

10614

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0344

AC:

2341

AN:

68028

Other (OTH)

AF:

0.0482

AC:

102

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

294

588

883

1177

1471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0348

Hom.:

321

Bravo

AF:

0.0423

TwinsUK

AF:

0.0299

AC:

111

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.0202

AC:

ESP6500EA

AF:

0.0368

AC:

316

ExAC

AF:

0.0515

AC:

6246

Asia WGS

AF:

0.110

AC:

380

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:38Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Benign:12

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Benign

Review Status:no assertion criteria provided

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 0.1049 (Asian), 0.01423 (African), 0.03694 (European), derived from 1000 genomes (2012-04-30). -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

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 02, 2014

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

High frequency in a 1kG or ESP population: 3.7 %. 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. -

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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. -

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

- -

Mar 15, 2011

Sharing Clinical Reports Project (SCRP)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:10Other:1

Sep 27, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

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

- -

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

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Jun 30, 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

#N/A -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 06, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:4

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 13, 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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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. -

Nov 04, 2014

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 02, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

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

- -

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

Benign:1

Apr 28, 2022

Fulgent Genetics, Fulgent Genetics

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

Breast carcinoma

Benign:1

Apr 18, 2019

Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Faculty of Medicine Ramathibodi Hospital, Mahidol University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.10

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-0.87

PhyloP100

0.50

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.086

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.046

D;D

Vest4

0.12

MPC

0.022

ClinPred

0.010

GERP RS

1.7

gMVP

0.12

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over