rs11571769

Variant names:

• chr13-32379413-G-A
• rs11571769
• NM_000059.4:c.8851G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32379413-G-A
• chr13-32379413-G-C
• chr13-32379413-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.8851G>A​(p.Ala2951Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00692 in 1,613,810 control chromosomes in the GnomAD database, including 134 homozygotes. 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. A2951G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0084 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (96 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:45 O:1
• Conservation: PhyloP100: 7.91
• Publications: 76 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=0.005076319).
• BP6: Variant 13-32379413-G-A is Benign according to our data. Variant chr13-32379413-G-A is described in ClinVar as Benign. ClinVar VariationId is 41570.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00841 (1281/152290) while in subpopulation AMR AF = 0.0508 (777/15300). AF 95% confidence interval is 0.0478. There are 38 homozygotes in GnomAd4. There are 724 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8851G>A	p.Ala2951Thr	missense_variant	Exon 22 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8851G>A	p.Ala2951Thr	missense_variant	Exon 22 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8482G>A	p.Ala2828Thr	missense_variant	Exon 22 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*909G>A		non_coding_transcript_exon_variant	Exon 21 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*909G>A		3_prime_UTR_variant	Exon 21 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00835 AC: 1270 AN: 152172 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00512

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00955 AC: 2395 AN: 250796 AF XY: 0.00886

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.0378

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.00677 AC: 9893 AN: 1461520 Hom.: 96 Cov.: 31 AF XY: 0.00681 AC XY: 4951 AN XY: 727048

African (AFR) AF: 0.00114 AC: 38 AN: 33458

American (AMR) AF: 0.0392 AC: 1751 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26120

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39662

South Asian (SAS) AF: 0.0146 AC: 1256 AN: 86188

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53412

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5764

European-Non Finnish (NFE) AF: 0.00574 AC: 6378 AN: 1111850

Other (OTH) AF: 0.00620 AC: 374 AN: 60368

GnomAD4 genome AF: 0.00841 AC: 1281 AN: 152290 Hom.: 38 Cov.: 33 AF XY: 0.00972 AC XY: 724 AN XY: 74480

African (AFR) AF: 0.00123 AC: 51 AN: 41554

American (AMR) AF: 0.0508 AC: 777 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4828

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00513 AC: 349 AN: 68008

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00536 Hom.: 18

Bravo AF: 0.00992

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00782 AC: 949

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00563

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:45 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:13

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.8851G>A variant is classified as Benign -

Jan 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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 14, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 02, 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. -

Oct 30, 2014

Pathway Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2016

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 0.036 (Admixed American/Latino), 0.0215 (South Asian), derived from 1000 genomes (2013-05-02). -

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

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2015

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:9 Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 30, 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

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 3.5% (402/11526) Latino chromosomes -

not provided Benign:6

Mar 30, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PM5, BP4, BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary cancer-predisposing syndrome Benign:5

Jan 06, 2016

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2017

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 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. -

Mar 20, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 30, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:5

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 04, 2014

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: 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

- -

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

- -

Malignant tumor of breast Benign:2

-

Center of Medical Genetics and Primary Health Care

Significance: Benign

Review Status: no assertion criteria provided

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 p.Ala2951Thr variant has been reported in our laboratory as well as in the literature in 36/5864 (0.006 frequency) proband chromosomes and in 1/1018 control chromosomes (0.001 frequency) (Bergthorsson_2001_11389159, Borg_2010_20104584, Saxena_2006_17018160, Lin_2003_12815053, Spitzer_2000_10699917, Serova-Sinilnikova_1997_9150172, Weber_2006_16685647, Wagner_1999_9971877, Waddell_2008_18497862). It is listed in dbSNP database (ID#:rs11571769) but no frequency information was provided, and so the prevalence of this variant in the general population is not known. The p.Ala2951 residue is conserved across vertebrate species, and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the p.Ala2951Thr variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In one study, this variant did not co-segregate with cancer in three families, and its frequency in 4680 clinical samples was similar to that of the control population (Deffenbaugh_2002_12215251). Notably, this variant has been identified in the UMD database in a total of 15 individuals who had a second pathogenic variant (9 with BRCA2 mutations and 6 with BRCA1) and associated with a breast or ovarian cancer phenotype, increasing the likelihood that the p.Ala2951Thr variant does not have clinical significance. In addition, Myriad calls this variant as a polymorphism. In summary, based on the above information this variant is classified as benign. -

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

- -

Ovarian cancer Pathogenic:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Jan 04, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related cancer predisposition Benign:1

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group D1 Benign:1

Jan 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	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0051	T;T
MetaSVM	Uncertain	-0.23	T
PhyloP100		7.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.51
MVP		0.89
MPC		0.16
ClinPred		0.020	T
GERP RS		5.6
gMVP		0.33
Mutation Taster		=94/6	polymorphism (auto)

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: rs11571769; hg19: chr13-32953550; COSMIC: COSV66463542; COSMIC: COSV66463542;