chr13-32333276-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000059.4(BRCA2):c.1798T>C(p.Tyr600His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,606,000 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. Y600F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:20O:1

Conservation

PhyloP100: 0.395

Publications

19 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058394074).

BP6

Variant 13-32333276-T-C is Benign according to our data. Variant chr13-32333276-T-C is described in ClinVar as Benign. ClinVar VariationId is 51197.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.1798T>C	p.Tyr600His	missense	Exon 10 of 27	NP_000050.3	A0A7P0T9D7
BRCA2	NM_001432077.1		c.1798T>C	p.Tyr600His	missense	Exon 10 of 27	NP_001419006.1	A0A7P0T9D7
BRCA2	NM_001406720.1		c.1798T>C	p.Tyr600His	missense	Exon 10 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.1798T>C	p.Tyr600His	missense	Exon 10 of 27	ENSP00000369497.3	P51587
BRCA2	ENST00000544455.6	TSL:1	c.1798T>C	p.Tyr600His	missense	Exon 10 of 27	ENSP00000439902.1	P51587
BRCA2	ENST00000530893.7	TSL:1	c.1429T>C	p.Tyr477His	missense	Exon 10 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes

AF:

0.00152

AC:

232

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00545

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000400

AC:

AN:

242486

AF XY:

0.000289

show subpopulations

Gnomad AFR exome

AF:

0.00554

Gnomad AMR exome

AF:

0.000212

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000126

AC:

183

AN:

1453686

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

723000

show subpopulations

African (AFR)

AF:

0.00473

AC:

155

AN:

32770

American (AMR)

AF:

0.000210

AC:

AN:

42862

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25810

East Asian (EAS)

AF:

0.00

AC:

AN:

39638

South Asian (SAS)

AF:

0.00

AC:

AN:

84150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1109492

Other (OTH)

AF:

0.000233

AC:

AN:

59996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00152

AC:

231

AN:

152314

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

108

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00541

AC:

225

AN:

41574

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000684

Hom.:

Bravo

AF:

0.00173

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000486

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Hereditary cancer-predisposing syndrome (4)

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

not specified (4)

Hereditary breast ovarian cancer syndrome (2)

BRCA2-related cancer predisposition (1)

Fanconi anemia (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.077

M_CAP

Benign

0.031

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.92

PhyloP100

0.40

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.58

REVEL

Benign

0.11

Sift

Benign

0.26

Sift4G

Benign

0.25

Vest4

0.28

MVP

0.79

MPC

0.022

ClinPred

0.0030

GERP RS

0.075

gMVP

0.15

Mutation Taster

=88/12

polymorphism

(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