13-32336266-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6_Very_StrongBP7

The NM_000059.4(BRCA2):c.1911T>C(p.Gly637Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,601,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. G637G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 splice_region, synonymous

Scores

Splicing: ADA: 0.01075

Clinical Significance

Benign reviewed by expert panel B:20

Conservation

PhyloP100: 1.88

Publications

5 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

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 13-32336266-T-C is Benign according to our data. Variant chr13-32336266-T-C is described in ClinVar as Benign. ClinVar VariationId is 136554.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=1.88 with no splicing effect.

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.1911T>C	p.Gly637Gly	splice_region synonymous	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
BRCA2	NM_001432077.1		c.1911T>C	p.Gly637Gly	splice_region synonymous	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
BRCA2	NM_001406720.1		c.1911T>C	p.Gly637Gly	splice_region synonymous	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.1911T>C	p.Gly637Gly	splice_region synonymous	Exon 11 of 27	ENSP00000369497.3	P51587
BRCA2	ENST00000544455.6	TSL:1	c.1911T>C	p.Gly637Gly	splice_region synonymous	Exon 11 of 27	ENSP00000439902.1	P51587
BRCA2	ENST00000530893.7	TSL:1	c.1542T>C	p.Gly514Gly	splice_region synonymous	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

156

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000279

AC:

AN:

240050

AF XY:

0.000223

show subpopulations

Gnomad AFR exome

AF:

0.00396

Gnomad AMR exome

AF:

0.0000944

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000842

AC:

122

AN:

1449026

Hom.:

Cov.:

AF XY:

0.0000597

AC XY:

AN XY:

720454

show subpopulations

African (AFR)

AF:

0.00312

AC:

102

AN:

32728

American (AMR)

AF:

0.0000958

AC:

AN:

41768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25436

East Asian (EAS)

AF:

0.00

AC:

AN:

39608

South Asian (SAS)

AF:

0.00

AC:

AN:

83620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5136

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1107824

Other (OTH)

AF:

0.000201

AC:

AN:

59768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00103

AC:

157

AN:

152276

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00363

AC:

151

AN:

41552

American (AMR)

AF:

0.000392

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000394

Hom.:

Bravo

AF:

0.00109

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Breast-ovarian cancer, familial, susceptibility to, 2 (3)

Hereditary breast ovarian cancer syndrome (3)

Hereditary cancer-predisposing syndrome (3)

not provided (2)

Familial cancer of breast (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

1.9

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.011

dbscSNV1_RF

Benign

0.098

SpliceAI score (max)

0.010

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