13-32394843-T-G

Variant summary

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

The NM_000059.4(BRCA2):​c.9411T>G​(p.Thr3137Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,613,996 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 (★★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 synonymous

Scores

2

Clinical Significance

Benign reviewed by expert panel B:10

Conservation

PhyloP100: -0.884
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BP6
Variant 13-32394843-T-G is Benign according to our data. Variant chr13-32394843-T-G is described in ClinVar as [Benign]. Clinvar id is 183987.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32394843-T-G is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.884 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.9411T>G p.Thr3137Thr synonymous_variant 25/27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.9411T>G p.Thr3137Thr synonymous_variant 25/275 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkuse as main transcriptc.9042T>G p.Thr3014Thr synonymous_variant 25/271 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkuse as main transcriptn.*1469T>G non_coding_transcript_exon_variant 24/262 ENSP00000506251.1 A0A7P0TAP7
BRCA2ENST00000614259.2 linkuse as main transcriptn.*1469T>G 3_prime_UTR_variant 24/262 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.000434
AC:
66
AN:
152186
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00546
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000553
AC:
139
AN:
251358
Hom.:
0
AF XY:
0.000545
AC XY:
74
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00448
Gnomad NFE exome
AF:
0.000352
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000210
AC:
307
AN:
1461810
Hom.:
0
Cov.:
31
AF XY:
0.000198
AC XY:
144
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00434
Gnomad4 NFE exome
AF:
0.0000567
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000434
AC:
66
AN:
152186
Hom.:
0
Cov.:
32
AF XY:
0.000767
AC XY:
57
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00546
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000247
Hom.:
0
Bravo
AF:
0.0000340
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Benign
Submissions summary: Benign:10
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingGeneDxSep 07, 2021This variant is associated with the following publications: (PMID: 10399947, 9150152, 9585608, 20104584) -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 18, 2016Variant summary: The BRCA2 c.9411T>G (p.Thr3137Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant, and 4/5 Alamut algorithms predict no significant change to splicing. This variant was found in 63/121504 control chromosomes, predominantly observed in the ExAC European (Finnish) subpopulation at a frequency of 0.0033303 (22/6606). 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 European (Finnish) origin. This variant has also been detected mainly in Finnish cancer patients from the literature, but without evidence of causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 30, 2019- -
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submittercurationSema4, Sema4Mar 16, 2022- -
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 13, 2017- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 20, 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. -
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:2
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 0.0033 (Finnish), derived from ExAC (2014-12-17). -
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 13, 2023- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 13, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.73
CADD
Benign
2.8
DANN
Benign
0.68

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: rs1799968; hg19: chr13-32968980; API