rs45525041

Variant names:

• chr13-32337274-G-A
• rs45525041
• NM_000059.4:c.2919G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32337274-G-A
• chr13-32337274-G-C
• chr13-32337274-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000059.4(BRCA2):​c.2919G>A​(p.Ser973Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,611,690 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. S973S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:24
• Conservation: PhyloP100: 0.315
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 13-32337274-G-A is Benign according to our data. Variant chr13-32337274-G-A is described in ClinVar as Benign. ClinVar VariationId is 51370.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.315 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.2919G>A	p.Ser973Ser	synonymous_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.2919G>A	p.Ser973Ser	synonymous_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.2550G>A	p.Ser850Ser	synonymous_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.2919G>A		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000358 AC: 89 AN: 248942 AF XY: 0.000438

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000323 AC: 472 AN: 1459544 Hom.: 1 Cov.: 33 AF XY: 0.000369 AC XY: 268 AN XY: 725998

African (AFR) AF: 0.0000301 AC: 1 AN: 33270

American (AMR) AF: 0.000226 AC: 10 AN: 44284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39626

South Asian (SAS) AF: 0.00142 AC: 122 AN: 85668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5748

European-Non Finnish (NFE) AF: 0.000275 AC: 306 AN: 1111298

Other (OTH) AF: 0.000299 AC: 18 AN: 60266

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41536

American (AMR) AF: 0.000131 AC: 2 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.000174

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:24

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:6

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 18, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA2 c.2919G>A (p.Ser973Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 54/120514 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.0017597 (29/16480). This frequency is about 2.35 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 South Asian origin. This variant is known to co-occur with multupe deleterious variants in literature (Lara_Biol Res_2012) and in UMD (BRCA1 c.5123C>A (p.Ala1708Glu), c.5266dup (p.Gln1756ProfsX74), c.2722G>T (p.Glu908X), and c.3485delA (p.Asp1162ValfsX48) and BRCA2 c.1184G>A (p.Trp395X)), strongly supporting for a benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as benign/likely beign. Taken together, this variant is classified as Benign. -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP4, BP7 -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:4

Jun 29, 2017

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0018 (South Asian), derived from ExAC (2014-12-17). -

Apr 28, 2017

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. -

Nov 24, 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. -

Mar 02, 2020

BRCAlab, Lund University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2003

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:4

Feb 06, 2014

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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2022

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3

Jun 01, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 28, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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 07, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary breast ovarian cancer syndrome Benign:3

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

- -

Oct 10, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Jun 15, 2020

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group D1 Benign:1

Apr 28, 2017

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. -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Ser973= variant was identified in 4 of 3750 proband chromosomes (frequency: 0.001) from Spanish, Cypriot, Greek, Italian and American individuals or families with FCCX (familial crc type X), and breast/ovarian (sporadic and familial) cancers and was not identified in 100 chromosomes from healthy individuals (Garre 2015, Hadjisavvas 2004, Konstantopoulou 2007, Minucci 2015, Borg 2010). The variant was also identified in dbSNP (ID: rs45525041) “With other allele”, ClinVar (classified benign, reviewed by an expert panel (June 2017); submitters: benign by ENIGMA, Invitae, GeneDx and Baylor Miraca Genetics Laboratories; likely benign by Ambry Genetics, CHEO, Counsyl, Illumina; and uncertain significance by BIC), Clinvitae (6x), LOVD 3.0 (1x), UMD-LSDB (36x as 3-uv, co-occurring with BRCA1 pathogenic variants: c.5123C>A; p.Ala1708Glu, c.5266dup; p.Gln1756ProfsX74, c.2722G>T; p.Glu908X), and BIC Database (1x, clinical importance unknown, classification pending). The variant was not identified in COGR, Cosmic, ARUP Laboratories, and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 88 of 275074 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Breakdown of the observations by population include Latino in 7 of 34050 chromosomes (freq. 0.0002), European Non-Finnish in 33 of 125900 chromosomes (freq. 0.0003), and South Asian in 48 of 30236 chromosomes (freq. 0.002); it was not seen in the East Asian, African, other, Ashkenazi Jewish, and European Finnish populations. The p.Ser973= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Familial cancer of breast Benign:1

Feb 23, 2017

Baylor Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.34
PhyloP100		0.32
Mutation Taster		=100/0	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: rs45525041; hg19: chr13-32911411;