rs45525041

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

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 (★★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

BRCA2
NM_000059.4 synonymous

Scores

2

Clinical Significance

Benign reviewed by expert panel U:1B:24

Conservation

PhyloP100: 0.315
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 51370.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337274-G-A is described in Lovd as [Likely_benign]. Variant chr13-32337274-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.315 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA2NM_000059.4 linkc.2919G>A p.Ser973Ser synonymous_variant 11/27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.2919G>A p.Ser973Ser synonymous_variant 11/275 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.2550G>A p.Ser850Ser synonymous_variant 11/271 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.2919G>A non_coding_transcript_exon_variant 10/262 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152028
Hom.:
0
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.000358
AC:
89
AN:
248942
Hom.:
0
AF XY:
0.000438
AC XY:
59
AN XY:
134788
show subpopulations
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 SAS exome
AF:
0.00159
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
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
Gnomad4 AMR exome
AF:
0.000226
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000505
Gnomad4 SAS exome
AF:
0.00142
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000275
Gnomad4 OTH exome
AF:
0.000299
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
13
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000221
Gnomad4 OTH
AF:
0.00
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:1Benign:24
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:4
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA2)Jan 24, 2003- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This 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. -
Benign, no assertion criteria providedclinical testingBRCAlab, Lund UniversityMar 02, 2020- -
Benign, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Jun 29, 2017Synonymous 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). -
Likely benign, criteria provided, single submitterliterature onlyCounsylNov 24, 2014- -
not specified Benign:5
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 16, 2018- -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJan 18, 2022- -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 06, 2014This 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. -
Likely benign, criteria provided, single submitterclinical testingCancer Genetics and Genomics Laboratory, British Columbia Cancer AgencyApr 18, 2017- -
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
not provided Benign:5
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2023BRCA2: BP4, BP7 -
Likely benign, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 18, 2016Variant 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. -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJun 01, 2015- -
Benign, criteria provided, single submittercurationSema4, Sema4Feb 07, 2021- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 28, 2014This 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. -
Hereditary breast ovarian cancer syndrome Benign:3
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateNov 16, 2021- -
Benign, criteria provided, single submitterclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.Oct 10, 2023- -
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJun 15, 2020- -
Fanconi anemia complementation group D1 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This 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
Benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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
Benign, criteria provided, single submitterclinical testingBaylor GeneticsFeb 23, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
1.0
DANN
Benign
0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs45525041; hg19: chr13-32911411; API