rs28897728

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP4BP6_Very_Strong

The NM_000059.4(BRCA2):c.4585G>A(p.Gly1529Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,613,772 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1529A) has been classified as Likely benign. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 1 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:33

Conservation

PhyloP100: 7.78

Publications

54 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):

BRCA2-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
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

Specifications for BRCA2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.28319556).

BP6

Variant 13-32338940-G-A is Benign according to our data. Variant chr13-32338940-G-A is described in ClinVar as Benign. ClinVar VariationId is 37910.Status of the report is reviewed_by_expert_panel, 3 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA2	NM_000059.4	MANE Select	c.4585G>A	p.Gly1529Arg	missense	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
BRCA2	NM_001432077.1		c.4585G>A	p.Gly1529Arg	missense	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
BRCA2	NM_001406720.1		c.4585G>A	p.Gly1529Arg	missense	Exon 11 of 27	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.4585G>A	p.Gly1529Arg	missense	Exon 11 of 27	ENSP00000369497.3	P51587
BRCA2	ENST00000544455.6	TSL:1	c.4585G>A	p.Gly1529Arg	missense	Exon 11 of 27	ENSP00000439902.1	P51587
BRCA2	ENST00000530893.7	TSL:1	c.4216G>A	p.Gly1406Arg	missense	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000765

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000391

AC:

AN:

250336

AF XY:

0.000413

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000636

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000679

AC:

992

AN:

1461560

Hom.:

Cov.:

AF XY:

0.000656

AC XY:

477

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33450

American (AMR)

AF:

0.000246

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26122

East Asian (EAS)

AF:

0.000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.000418

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000781

AC:

868

AN:

1111876

Other (OTH)

AF:

0.000911

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.000460

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41534

American (AMR)

AF:

0.000785

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000765

AC:

AN:

67990

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000608

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 2 (12)

not specified (6)

not provided (5)

Hereditary cancer-predisposing syndrome (4)

Hereditary breast ovarian cancer syndrome (3)

Breast and/or ovarian cancer (2)

BRCA2-related disorder (1)

Fanconi anemia complementation group D1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.28

MetaSVM

Uncertain

0.60

PhyloP100

7.8

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Vest4

0.53

MutPred

0.95

Gain of MoRF binding (P = 0.0081)

MVP

0.97

MPC

0.17

ClinPred

0.28

GERP RS

5.7

gMVP

0.60

Mutation Taster

=23/77

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over