chr13-32397030-G-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.9634G>C(p.Gly3212Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3212E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:15O:1

Conservation

PhyloP100: 2.13

Publications

18 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):

breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
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=0.007734239).

BP6

Variant 13-32397030-G-C is Benign according to our data. Variant chr13-32397030-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 38257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.9634G>C	p.Gly3212Arg	missense_variant	Exon 26 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
BRCA2	ENST00000380152.8 link	c.9634G>C	p.Gly3212Arg	missense_variant	Exon 26 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7 link	c.9265G>C	p.Gly3089Arg	missense_variant	Exon 26 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2 link	n.*1692G>C		non_coding_transcript_exon_variant	Exon 25 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2 link	n.*1692G>C		3_prime_UTR_variant	Exon 25 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

203

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00476

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.000478

GnomAD2 exomes

AF:

0.000370

AC:

AN:

251338

AF XY:

0.000265

show subpopulations

Gnomad AFR exome

AF:

0.00535

Gnomad AMR exome

AF:

0.000145

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:

0.000163

GnomAD4 exome

AF:

0.000116

AC:

170

AN:

1461734

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00436

AC:

146

AN:

33466

American (AMR)

AF:

0.000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111928

Other (OTH)

AF:

0.000232

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.00133

AC:

203

AN:

152276

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00474

AC:

197

AN:

41546

American (AMR)

AF:

0.000327

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000138

Hom.:

Bravo

AF:

0.00133

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000511

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2Benign:3

Mar 24, 2008

Sharing Clinical Reports Project (SCRP)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 03, 2014

Counsyl

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Jul 17, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 17, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15744044, 11030418, 12491487, 25556971, 24728327, 28814288, 30362333, 18284688, 23231788, 19491284, 22034289) -

Jul 11, 2017

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary cancer-predisposing syndrome

Benign:3

Sep 11, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

May 24, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 08, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Jan 16, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 24, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:2

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BRCA2, p.Gly3212Arg variant was identified in 12 of 1272 proband chromosomes (frequency: 0.009) from individuals or families with breast cancer (Fackenthal 2012, Trujillano 2015). The variant was also identified in dbSNP (ID: rs55775473) as â€šÃ„Ãºotherâ€šÃ„Ã¹, Clinvitae database (classified as benign by Invitae; classified as likely benign by ClinVar), the ClinVar database (classified as benign by Invitae; classified as likely benign by GeneDx, Ambry Genetics, Counsyl, MMGLUM; classified as uncertain significance by SCRP, BIC), the BIC database (10x with unknown clinical importance), UMD (36x with an â€šÃ„Ãºunclassified variantâ€šÃ„Ã¹ classification) and Fanconi Anemia Mutation Database (LOVD). In UMD the variant was identified with co-occurring pathogenic BRCA2 variants (c.2612C>A, p.Ser871X and c.1310_1313delAAGA, p.Lys437IlefsX22), increasing the likelihood that the p.Gly3212Arg variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 12 of 5000 chromosomes (frequency: 0.0024), the NHLBI GO Exome Sequencing Project in 19 of 4406 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 62 of 121384 chromosomes (freq. 0.0005) in the following populations: African in 60 of 10406 chromosomes (freq. 0.006) and Latino in 2 of 11568 chromosomes (freq. 0.0002), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Gly3212 residue is conserved across mammals and other organisms, and one out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; loss of splicing site at a non-splice site consensus sequence. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.33

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.0077

T;T

MetaSVM

Benign

-0.94

PhyloP100

2.1

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.15

Sift

Benign

0.071

T;T

Sift4G

Uncertain

0.0080

D;D

Vest4

0.34

MutPred

0.33

Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);

MVP

0.84

MPC

0.064

ClinPred

0.016

GERP RS

3.0

gMVP

0.19

Mutation Taster

=78/22

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over