rs58627922

Variant names:

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.7397T>C(p.Val2466Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,613,598 control chromosomes in the GnomAD database, including 800,969 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V2466V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.98 ( 73292 hom., cov: 32)

Exomes 𝑓: 1.0 ( 727677 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:14O:1

Conservation

PhyloP100: 2.49

Publications

154 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=8.148477E-7).

BP6

Variant 13-32355250-T-C is Benign according to our data. Variant chr13-32355250-T-C is described in ClinVar as Benign. ClinVar VariationId is 133738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.7397T>C	p.Val2466Ala	missense_variant	Exon 14 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.7397T>C	p.Val2466Ala	missense_variant	Exon 14 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7028T>C	p.Val2343Ala	missense_variant	Exon 14 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.7397T>C		non_coding_transcript_exon_variant	Exon 13 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.981

AC:

149241

AN:

152192

Hom.:

73240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.933

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.993

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.978

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.985

GnomAD2 exomes

AF:

0.995

AC:

249881

AN:

251168

AF XY:

0.996

show subpopulations

Gnomad AFR exome

AF:

0.933

Gnomad AMR exome

AF:

0.996

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.997

GnomAD4 exome

AF:

0.998

AC:

1458237

AN:

1461288

Hom.:

727677

Cov.:

AF XY:

0.998

AC XY:

725661

AN XY:

726992

show subpopulations

African (AFR)

AF:

0.930

AC:

31114

AN:

33458

American (AMR)

AF:

0.996

AC:

44527

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26125

AN:

26126

East Asian (EAS)

AF:

1.00

AC:

39634

AN:

39634

South Asian (SAS)

AF:

1.00

AC:

86208

AN:

86222

European-Finnish (FIN)

AF:

1.00

AC:

53414

AN:

53414

Middle Eastern (MID)

AF:

0.995

AC:

5734

AN:

5764

European-Non Finnish (NFE)

AF:

1.00

AC:

1111380

AN:

1111588

Other (OTH)

AF:

0.996

AC:

60101

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

152

303

455

606

758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21660

43320

64980

86640

108300

<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:

0.981

AC:

149351

AN:

152310

Hom.:

73292

Cov.:

AF XY:

0.981

AC XY:

73073

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.933

AC:

38754

AN:

41548

American (AMR)

AF:

0.993

AC:

15199

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5177

AN:

5178

South Asian (SAS)

AF:

1.00

AC:

4828

AN:

4830

European-Finnish (FIN)

AF:

1.00

AC:

10626

AN:

10626

Middle Eastern (MID)

AF:

0.976

AC:

287

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68015

AN:

68032

Other (OTH)

AF:

0.985

AC:

2083

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

144

288

433

577

721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

916

1832

2748

3664

4580

<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:

0.992

Hom.:

218643

Bravo

AF:

0.978

TwinsUK

AF:

1.00

AC:

3707

ALSPAC

AF:

0.999

AC:

3852

ESP6500AA

AF:

0.935

AC:

4119

ESP6500EA

AF:

0.999

AC:

8593

ExAC

AF:

0.994

AC:

120636

Asia WGS

AF:

0.996

AC:

3460

AN:

3474

EpiCase

AF:

0.999

EpiControl

AF:

0.999

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7Other:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Oct 23, 2015

Eurofins Ntd Llc (ga)

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

- -

Feb 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This is a RefSeq error. The reference base (c.7397T) is the minor allele. This a llele (T) has been identified in 6.7% (696/10392) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1695 47) and thus meets criteria to be classified as benign. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 2

Benign:2

May 28, 2019

Mendelics

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

- -

not provided

Benign:2

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary breast ovarian cancer syndrome

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), 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

- -

Breast ductal adenocarcinoma

Uncertain:1

Jul 20, 2015

Next Generation Diagnostics, Novartis Institutes for BioMedical Research, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

BRCA2-related cancer predisposition

Benign:1

Oct 03, 2024

All of Us Research Program, National Institutes of Health

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

0.051

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.68

CADD

Benign

8.7

(source)

DANN

Benign

0.17

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.00045

MetaRNN

Benign

8.1e-7

T;T

MetaSVM

Benign

-0.93

PhyloP100

2.5

PrimateAI

Benign

0.27

PROVEAN

Benign

0.62

N;N

REVEL

Benign

0.091

Sift

Benign

1.0

T;T

Sift4G

Benign

0.70

T;T

Vest4

0.035

MPC

0.021

ClinPred

0.0074

GERP RS

5.1

gMVP

0.17

Mutation Taster

=100/0

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