Genetic Variant BRCA2:p.Thr1915Met (chr13-32340099-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000059.4(BRCA2):c.5744C>T(p.Thr1915Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,613,612 control chromosomes in the GnomAD database, including 679 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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. T1915A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 31 hom., cov: 33)

Exomes 𝑓: 0.027 ( 648 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:41O:1

Conservation

PhyloP100: -1.10

Publications

113 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026650429).

BP6

Variant 13-32340099-C-T is Benign according to our data. Variant chr13-32340099-C-T is described in ClinVar as Benign. ClinVar VariationId is 41556.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0179 (2719/152214) while in subpopulation NFE AF = 0.0306 (2081/67978). AF 95% confidence interval is 0.0295. There are 31 homozygotes in GnomAd4. There are 1269 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 AD,AR gene

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.5744C>T	p.Thr1915Met	missense	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
BRCA2	NM_001432077.1		c.5744C>T	p.Thr1915Met	missense	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
BRCA2	NM_001406720.1		c.5744C>T	p.Thr1915Met	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.5744C>T	p.Thr1915Met	missense	Exon 11 of 27	ENSP00000369497.3	P51587
BRCA2	ENST00000544455.6	TSL:1	c.5744C>T	p.Thr1915Met	missense	Exon 11 of 27	ENSP00000439902.1	P51587
BRCA2	ENST00000530893.7	TSL:1	c.5375C>T	p.Thr1792Met	missense	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2719

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00579

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.00754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0306

Gnomad OTH

AF:

0.0168

GnomAD2 exomes

AF:

0.0176

AC:

4420

AN:

250908

AF XY:

0.0180

show subpopulations

Gnomad AFR exome

AF:

0.00543

Gnomad AMR exome

AF:

0.00892

Gnomad ASJ exome

AF:

0.0160

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00866

Gnomad NFE exome

AF:

0.0290

Gnomad OTH exome

AF:

0.0196

GnomAD4 exome

AF:

0.0274

AC:

40071

AN:

1461398

Hom.:

648

Cov.:

AF XY:

0.0271

AC XY:

19723

AN XY:

726980

show subpopulations

African (AFR)

AF:

0.00433

AC:

145

AN:

33474

American (AMR)

AF:

0.00892

AC:

399

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

436

AN:

26130

East Asian (EAS)

AF:

0.000151

AC:

AN:

39666

South Asian (SAS)

AF:

0.00985

AC:

849

AN:

86228

European-Finnish (FIN)

AF:

0.0115

AC:

615

AN:

53368

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0325

AC:

36103

AN:

1111676

Other (OTH)

AF:

0.0240

AC:

1447

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

2169

4338

6507

8676

10845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1360

2720

4080

5440

6800

<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:

0.0179

AC:

2719

AN:

152214

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1269

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00578

AC:

240

AN:

41552

American (AMR)

AF:

0.0114

AC:

175

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00850

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00754

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0306

AC:

2081

AN:

67978

Other (OTH)

AF:

0.0166

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

142

284

426

568

710

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0256

Hom.:

202

Bravo

AF:

0.0174

TwinsUK

AF:

0.0294

AC:

109

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0291

AC:

250

ExAC

AF:

0.0179

AC:

2167

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0261

EpiControl

AF:

0.0258

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 (12)

not provided (6)

Hereditary breast ovarian cancer syndrome (5)

Hereditary cancer-predisposing syndrome (5)

Familial cancer of breast (2)

Breast neoplasm (1)

Fanconi anemia complementation group D1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.032

(source)

DANN

Benign

0.063

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0024

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

PhyloP100

-1.1

PrimateAI

Benign

0.22

PROVEAN

Benign

2.7

REVEL

Benign

0.14

Sift

Benign

0.33

Sift4G

Benign

0.38

Vest4

0.065

MPC

0.020

ClinPred

0.0068

GERP RS

0.62

gMVP

0.14

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over