rs4987048

Variant names:

• chr13-32340059-G-A
• rs4987048
• NM_000059.4:c.5704G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32340059-G-A
• chr13-32340059-G-C
• chr13-32340059-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000059.4(BRCA2):​c.5704G>A​(p.Asp1902Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,613,726 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. D1902V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0059 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (4 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:34 O:1
• Conservation: PhyloP100: 0.114
• Publications: 33 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045973957).
• BP6: Variant 13-32340059-G-A is Benign according to our data. Variant chr13-32340059-G-A is described in ClinVar as Benign. ClinVar VariationId is 51912.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0059 (899/152252) while in subpopulation AFR AF = 0.0209 (869/41556). AF 95% confidence interval is 0.0198. There are 9 homozygotes in GnomAd4. There are 416 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5704G>A	p.Asp1902Asn	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5704G>A	p.Asp1902Asn	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5335G>A	p.Asp1779Asn	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5704G>A		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00589 AC: 896 AN: 152134 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.0000441

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00139 AC: 348 AN: 250772 AF XY: 0.00108

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000588 AC: 860 AN: 1461474 Hom.: 4 Cov.: 45 AF XY: 0.000517 AC XY: 376 AN XY: 727040

African (AFR) AF: 0.0209 AC: 699 AN: 33470

American (AMR) AF: 0.000738 AC: 33 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111824

Other (OTH) AF: 0.00137 AC: 83 AN: 60376

GnomAD4 genome AF: 0.00590 AC: 899 AN: 152252 Hom.: 9 Cov.: 33 AF XY: 0.00559 AC XY: 416 AN XY: 74446

African (AFR) AF: 0.0209 AC: 869 AN: 41556

American (AMR) AF: 0.00131 AC: 20 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67998

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00229 Hom.: 9

Bravo AF: 0.00656

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00166 AC: 201

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:34 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:10

Oct 29, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2015

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.01626 (African), derived from 1000 genomes (2012-04-30). -

Sep 21, 2015

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2014

Counsyl

Significance: 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. -

Jan 29, 2016

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Asp1902Asn was identified in 2 of 4284 chromosomes (frequency: 0.0005) from individuals with breast cancer, and was absent in control chromosomes from these studies (Borg 2010, Fackenthal 2005). It is listed in dbSNP (ID#: rs4987048) with a “global minor allele frequency" of 0.004 (1000 Genomes), and in the Exome Variant Server ESP project with a frequency of 0.018 in African American alleles. It is also reported in several populations from the HapMap project, including: HAPMAP-MEX (frequency: 0.031), HAPMAP-LWK (frequency: 0.034), and HapMap-HCB (frequency: 0.038), increasing the likelihood that this is a low frequency benign variant in certain populations of origin. This variant was identified in LOVD, in BIC 87X with no clinical importance, and in UMD 10X as a “neutral” variant where it was reported to co-occur with known pathogenic mutations in BRCA1 and BRCA2 (BRCA2 c.994dup (p.Ile332AsnfsX4), BRCA1 c.3607C>T (p.Arg1203X), BRCA1 c.755_761del (p.Arg252LeufsX44)), further increasing the likelihood that this variant is benign. The p.Asp1902 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein, although this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, this variant is classified as benign. -

not specified Benign:8 Other:1

Oct 03, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2017

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 11, 2019

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2014

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2021

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 16, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Jun 23, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP4, BS1, BS2 -

Hereditary cancer-predisposing syndrome Benign:3

Dec 21, 2015

Vantari Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 10, 2015

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. -

Breast and/or ovarian cancer Uncertain:1 Benign:1

Dec 04, 2002

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 26, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Benign:2

Feb 23, 2017

Baylor Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group D1 Benign:1

Oct 29, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Uncertain	1.0
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.083	N
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.93	T
PhyloP100		0.11
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.095
Sift	Benign	0.17	T;T
Sift4G	Benign	0.48	T;T
Vest4		0.35
MVP		0.83
MPC		0.023
ClinPred		0.012	T
GERP RS		4.0
gMVP		0.20
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs4987048; hg19: chr13-32914196;