chr13-32346895-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM5BP4_StrongBP6

The NM_000059.4(BRCA2):c.7006C>T(p.Arg2336Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,604,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/22 in silico tools predict 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2336H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense, splice_region

Scores

Splicing: ADA: 0.0002450

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:3

Conservation

PhyloP100: 0.0390

Publications

27 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: Likely_benign. The variant received -3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32346896-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38077.Status of the report is reviewed_by_expert_panel, 3 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.049040914).

BP6

Variant 13-32346895-C-T is Benign according to our data. Variant chr13-32346895-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96845.

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.7006C>T	p.Arg2336Cys	missense splice_region	Exon 13 of 27	NP_000050.3	A0A7P0T9D7
BRCA2	NM_001432077.1		c.7006C>T	p.Arg2336Cys	missense splice_region	Exon 13 of 27	NP_001419006.1	A0A7P0T9D7
BRCA2	NM_001406720.1		c.7006C>T	p.Arg2336Cys	missense splice_region	Exon 13 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.7006C>T	p.Arg2336Cys	missense splice_region	Exon 13 of 27	ENSP00000369497.3	P51587
BRCA2	ENST00000544455.6	TSL:1	c.7006C>T	p.Arg2336Cys	missense splice_region	Exon 13 of 27	ENSP00000439902.1	P51587
BRCA2	ENST00000530893.7	TSL:1	c.6637C>T	p.Arg2213Cys	missense splice_region	Exon 13 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000807

AC:

AN:

247890

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1452160

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

722552

show subpopulations

African (AFR)

AF:

0.0000601

AC:

AN:

33274

American (AMR)

AF:

0.0000677

AC:

AN:

44288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25996

East Asian (EAS)

AF:

0.00

AC:

AN:

39428

South Asian (SAS)

AF:

0.0000236

AC:

AN:

84904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000814

AC:

AN:

1106278

Other (OTH)

AF:

0.00

AC:

AN:

60042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

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:

0.0000854

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41552

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67936

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.00

Hom.:

Bravo

AF:

0.0000453

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 2 (4)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

BRCA2-related disorder (1)

Breast and/or ovarian cancer (1)

Hereditary breast ovarian cancer syndrome (1)

not specified (1)

Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.62

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0044

M_CAP

Benign

0.059

MetaRNN

Benign

0.049

MetaSVM

Benign

-1.0

PhyloP100

0.039

PrimateAI

Benign

0.21

PROVEAN

Benign

1.8

REVEL

Benign

0.24

Sift

Benign

0.71

Sift4G

Benign

0.15

Vest4

0.36

MutPred

0.46

Loss of disorder (P = 0.0484)

MVP

0.70

MPC

0.022

ClinPred

0.024

GERP RS

-5.6

gMVP

0.23

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00024

dbscSNV1_RF

Benign

0.020

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

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