NM_000059.4:c.9038C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_000059.4(BRCA2):​c.9038C>T​(p.Thr3013Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000487 in 1,613,402 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00052 ( 2 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

3
13

Clinical Significance

Benign reviewed by expert panel U:2B:27

Conservation

PhyloP100: 3.67
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 -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10728961).
BP6
Variant 13-32379834-C-T is Benign according to our data. Variant chr13-32379834-C-T is described in ClinVar as [Benign]. Clinvar id is 38205.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379834-C-T is described in Lovd as [Benign]. Variant chr13-32379834-C-T is described in Lovd as [Pathogenic].
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.9038C>T p.Thr3013Ile missense_variant Exon 23 of 27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.9038C>T p.Thr3013Ile missense_variant Exon 23 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.8669C>T p.Thr2890Ile missense_variant Exon 23 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.*1096C>T non_coding_transcript_exon_variant Exon 22 of 26 2 ENSP00000506251.1 A0A7P0TAP7
BRCA2ENST00000614259.2 linkn.*1096C>T 3_prime_UTR_variant Exon 22 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.000217
AC:
33
AN:
152180
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000252
AC:
63
AN:
250466
Hom.:
1
AF XY:
0.000318
AC XY:
43
AN XY:
135386
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000870
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000487
Gnomad OTH exome
AF:
0.000328
GnomAD4 exome
AF:
0.000515
AC:
753
AN:
1461104
Hom.:
2
Cov.:
32
AF XY:
0.000497
AC XY:
361
AN XY:
726868
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000629
Gnomad4 OTH exome
AF:
0.000729
GnomAD4 genome
AF:
0.000217
AC:
33
AN:
152298
Hom.:
0
Cov.:
33
AF XY:
0.000188
AC XY:
14
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000512
Hom.:
0
Bravo
AF:
0.000264
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000582
AC:
5
ExAC
AF:
0.000231
AC:
28
EpiCase
AF:
0.000654
EpiControl
AF:
0.000534

ClinVar

Significance: Benign
Submissions summary: Uncertain:2Benign:27
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:7
Jun 18, 2019
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 1.80E-06 -

May 29, 2002
Breast Cancer Information Core (BIC) (BRCA2)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 03, 2014
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

Mar 15, 2006
Sharing Clinical Reports Project (SCRP)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 31, 2017
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Likely 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

- -

not specified Uncertain:2Benign:4
Jul 13, 2018
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
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

- -

Jun 23, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
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: ClinVar: 8 B/LB -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 20, 2017
PreventionGenetics, part of Exact Sciences
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.Thr3013Ile variant was identified in 5 of 2946 proband chromosomes (frequency: 0.002) from individuals with breast or ovarian cancer (Claes 2004, Diez 2003, Kim 2005). This variant was listed in dbSNP (ID: rs28897755) “With probable-non-pathogenic allele”, and in the Exome Variant Server ESP project with a frequency of 0.0004. It was identified in several populations from the HapMap project, including: HAPMAP-MEX (frequency: 0.03), HapMap-JPT (frequency: 0.012), and HapMap-HCB (frequency: 0.012), increasing the likelihood that this is a low frequency benign variant in certain populations of origin. The variant was also identified in the following databases: HGMD, LOVD, BIC (53X with no clinical importance), and UMD (13X as a neutral variant). In UMD it was twice reported to co-occur with pathogenic mutations in the BRCA1 or BRCA2 genes (BRCA2 c.1257delT (p.Cys419TrpfsX11), BRCA1 c.5266dup (p.Gln1756ProfsX74)), increasing the likelihood that this variant does not have clinical significance. In addition, in silico studies and functional studies predict this that this variant has a neutral effect on BRCA2 protein function (Guidugli 2013, Karachin 2008). The p.Thr3013 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein but this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Hereditary cancer-predisposing syndrome Benign:5
Sep 07, 2017
True Health Diagnostics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 23, 2018
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Likely 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. -

Mar 09, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 10, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

not provided Benign:4
Jun 20, 2017
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 13, 2012
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Oct 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BRCA2: BP4, BS3:Supporting -

Feb 02, 2018
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The BRCA2 c.9038C>T; p.Thr3013Ile variant (rs28897755) has been reported in the literature in individuals with a personal or family history of hereditary breast and ovarian cancer (Houdayer 2012, Malone 2000, Sanz 2010). However, this variant has also been found incidentally in an individual with no personal or family history of cancer (Johnston 2012). This variant is reported with conflicting interpretations of pathogenicity in ClinVar, with most sources classifying as benign or likely benign (Variation ID: 38205) and is seen in the general population at an overall frequency of 0.02% (65/276280 alleles, including 1 homozygote) in the Genome Aggregation Database. The threonine at codon 3013 is moderately conserved but computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to have no impact on protein function. In agreement with this, functional analysis of this variant protein shows no defects in DNA double-strand break repair using a cell-based homology directed repair assay (Guidugli 2013). Based on the above information, this variant is considered likely benign. REFERENCES Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology directed repair activity. Cancer Res. 2013 Jan 1; 73(1): 265–275. Houdayer C et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat. 2012 Aug;33(8):1228-38. Johnston J et al. Secondary Variants in Individuals Undergoing Exome Sequencing: Screening of 572 Individuals Identifies High-Penetrance Mutations in Cancer-Susceptibility Genes. Am J Hum Genet. 2012 Jul 13; 91(1): 97–108. Malone K et al. Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer. 2000 Mar 15;88(6):1393-402. Sanz D et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010 Mar 15;16(6):1957-67. -

Hereditary breast ovarian cancer syndrome Benign:2
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1
Feb 05, 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. -

BRCA2-related cancer predisposition Benign:1
Sep 23, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast neoplasm Benign:1
Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Familial cancer of breast Benign:1
Aug 02, 2021
Genetics and Molecular Pathology, SA Pathology
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The BRCA2 c.9038C>T variant is classified as Benign (BS1, BS3, BP4, BP6) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.017
T
BayesDel_noAF
Uncertain
0.070
CADD
Benign
22
DANN
Uncertain
1.0
Eigen
Benign
-0.10
Eigen_PC
Benign
-0.15
FATHMM_MKL
Benign
0.47
N
M_CAP
Benign
0.075
D
MetaRNN
Benign
0.11
T;T
MetaSVM
Benign
-0.80
T
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.83
N;N
REVEL
Uncertain
0.37
Sift
Benign
0.036
D;D
Sift4G
Benign
0.081
T;T
Vest4
0.44
MVP
0.87
MPC
0.13
ClinPred
0.043
T
GERP RS
3.9
gMVP
0.41

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: rs28897755; hg19: chr13-32953971; COSMIC: COSV66450260; COSMIC: COSV66450260; API