rs45491005

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.5768A>C(p.Asp1923Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,613,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. D1923N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:21

Conservation

PhyloP100: -0.761

Publications

16 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=0.0141219795).

BP6

Variant 13-32340123-A-C is Benign according to our data. Variant chr13-32340123-A-C is described in ClinVar as Benign. ClinVar VariationId is 37995.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.5768A>C	p.Asp1923Ala	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.5768A>C	p.Asp1923Ala	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.5399A>C	p.Asp1800Ala	missense_variant	Exon 11 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.5768A>C		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000243

AC:

AN:

250518

AF XY:

0.000192

show subpopulations

Gnomad AFR exome

AF:

0.00365

Gnomad AMR exome

AF:

0.0000581

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:

0.0000979

AC:

143

AN:

1460936

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

726692

show subpopulations

African (AFR)

AF:

0.00410

AC:

137

AN:

33402

American (AMR)

AF:

0.0000449

AC:

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111622

Other (OTH)

AF:

0.0000663

AC:

AN:

60344

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

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:

0.000748

AC:

114

AN:

152336

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00267

AC:

111

AN:

41590

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000393

Hom.:

Bravo

AF:

0.00103

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000280

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:21

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:6

Jan 07, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10800284, 23555315, 21520273, 18284688, 25348012, 25801821, 23704879, 22034289, 20104584) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 28, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:3

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 23, 2009

Sharing Clinical Reports Project (SCRP)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 18, 2019

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00310 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13). -

Hereditary breast ovarian cancer syndrome

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 27, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 16, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The BRCA2 c.5768A>C (p.Asp1923Ala) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 34/121054 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0032372 (33/10194). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. One co-occurrence with BRCA1 c.2679_2682delGAAA was found in one individual (BRCA Share database). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as likely benign. -

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hereditary cancer-predisposing syndrome

Benign:3

Jan 07, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 2014

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. -

Feb 17, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Benign:1

Mar 05, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast and/or ovarian cancer

Benign:1

Aug 31, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BRCA2-related cancer predisposition

Benign:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BRCA2-related disorder

Benign:1

Aug 28, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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.Asp1923Ala variant was identified in 12 of 5074 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer (Borg 2010, Fackenthal 2012). The variant was also identified in dbSNP (ID: rs45491005) as â€šÃ„ÃºWith Uncertain significance, other alleleâ€šÃ„Ã¹, the ClinVar database (classified as benign by Invitae, Ambry Genetics, SCRP; likely benign by GeneDx, MMGLUM; uncertain significance by BIC), COGR database (classified as uncertain significance by one clinical laboratory), the BIC database (9x with unknown importance) and UMD (29x with a â€šÃ„Ãºlikely neutralâ€šÃ„Ã¹ classification). In UMD the variant was identified with a co-occurring pathogenic BRCA1 (c.2679_2682delGAAA, p.Lys893AsnfsX106) and BRCA2 variants (c.7558C>T, p.Arg2520X), increasing the likelihood that the p.Asp1923Ala variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), the NHLBI GO Exome Sequencing Project in 13 of 4406 African American alleles, the Exome Aggregation Consortium database (August 8th 2016) and the Genome Aggregation Database (October 3, 2017) in 78 of 276432 chromosomes (freq. 0.0003). The variant was observed in the following populations: in 75 of 24020 African chromosomes (freq. 0.0003), â€šÃ„ÃºOtherâ€šÃ„Ã¹ in 2 of 6450 chromosomes (freq. 0.0003), and Latino in 1 of 34326 chromosomes (freq. 0.00001), but was not seen in Asian, European, or Finnish populations. The p.Asp1923 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. One study predicted the variant to abolish kinase binding; however this was only based on in silico results (Tram 2013). 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

0.14

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

7.8

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.065

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.82

PhyloP100

-0.76

PrimateAI

Benign

0.24

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.025

D;D

Sift4G

Benign

0.52

T;T

Vest4

0.43

MVP

0.90

MPC

0.15

ClinPred

0.14

GERP RS

2.9

gMVP

0.31

Mutation Taster

=84/16

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