chr13-32356536-C-T

Variant names:

Variant summary

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

The NM_000059.4(BRCA2):c.7544C>T(p.Thr2515Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000542 in 1,614,246 control chromosomes in the GnomAD database, including 4 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. T2515T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00047 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00055 ( 3 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:32O:1

Conservation

PhyloP100: 4.22

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]

BRCA2 links:

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=0.17741424).

BP6

Variant 13-32356536-C-T is Benign according to our data. Variant chr13-32356536-C-T is described in ClinVar as [Benign]. Clinvar id is 38102.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32356536-C-T is described in Lovd as [Benign]. Variant chr13-32356536-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.7544C>T	p.Thr2515Ile	missense_variant	Exon 15 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.7544C>T	p.Thr2515Ile	missense_variant	Exon 15 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7175C>T	p.Thr2392Ile	missense_variant	Exon 15 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.7544C>T		non_coding_transcript_exon_variant	Exon 14 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.000466

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000581

AC:

146

AN:

251294

Hom.:

AF XY:

0.000560

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.000898

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000550

AC:

804

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000583

AC XY:

424

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.00105

Gnomad4 NFE exome

AF:

0.000606

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000466

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00783

Hom.:

842

Bravo

AF:

0.000351

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000749

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:32Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Benign:10

Aug 10, 2015

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 = 0.0000643 -

Mar 02, 2020

BRCAlab, Lund University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2014

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

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

- -

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 08, 2019

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. -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1Benign:5Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

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

- -

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

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 16, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: ClinVar: 7 labs classify as B/LB -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Thr2515Ile variant was identified in 4 of 3460 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Campos 2001, Diez 2003, Plaschke 2000, Meindl 2002), and was present in 3 of 830 control chromosomes (frequency: 0.004) from healthy individuals (Cvok 2008, Meindl 2002). The variant was also identified in several database searches, including: GeneInsight â€šÃ„Ã¬ COGR (submitted by a clinical laboratory as â€šÃ„Ãºunclassifiedâ€šÃ„Ã¹), UMD/BRCA Share (37X with a â€šÃ„Ãºlikely neutralâ€šÃ„Ã¹ classification), ARUP Laboratories BRCA Mutation Database (classified as â€šÃ„Ãºnot pathogenic or of no clinical significanceâ€šÃ„Ã¹), BIC (72X as a variant with no clinical significance), LOVD â€šÃ„Ã¬ IARC (classified as â€šÃ„Ãºnot pathogenic or of no clinical significanceâ€šÃ„Ã¹), and ClinVar (classified as â€šÃ„Ãºbenignâ€šÃ„Ã¹ by four submitters and â€šÃ„Ãºlikely benignâ€šÃ„Ã¹ by three submitters). In the UMD/BRCA Share database, three samples were listed with co-occurring pathogenic BRCA1 or BRCA2 variants, increasing the likelihood that the p.Thr2515Ile variant is not clinically significant. In addition, the variant was identified at polymorphic frequencies in three HAPMAP populations (HAPMAP-MEX (Mexican), HAPMAP-JPT (Japanese), HAPMAP-HCB (Han Chinese)) listed in dbSNP (ID: rs28897744), and Myriad classifies this variant as a polymorphism (personal communication). The p.Thr2515 residue is not conserved across mammals and other organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. One study utilizing in vitro assays suggests that the variant may impact certain BRCA2 functions and cellular localization; however, segregation analysis of nine pedigrees in this same study found low odds in favour of disease causality (Wu 2005). Two multifactorial analysis studies and one bioinformatics study predict the variant to be neutral or have no clinical significance (Karchin 2008, Lindor 2012, Spurdle 2008). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, RNA analysis done in a study by Campos (2003) found that the variant did not alter splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

not provided

Benign:7

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 17, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21990134, 24728327, 28288110, 28324225, 24082139, 30611917, 25556971, 18844490, 19043619, 9971877, 12955719, 12955716, 12161607, 25782689, 23884293, 10978364, 17250666, 22703879, 21702907, 24323938, 15695382, 27376475, 28263838, 27153395, 29061375, 28866612, 28283652, 26517685, 30696104, 29988080, 31131559, 32444794, 29884841) -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BS1, BS2 -

Jul 27, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:4

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. -

Dec 16, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

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

- -

Sep 25, 2020

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 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 03, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer

Benign:1

Jun 01, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Fanconi anemia complementation group D1

Benign:1

Oct 08, 2019

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

0.27

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.92

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.18

T;T

MetaSVM

Uncertain

0.18

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.57

Sift

Benign

0.064

T;T

Sift4G

Benign

0.097

T;T

Vest4

0.46

MVP

0.95

MPC

0.16

ClinPred

0.076

GERP RS

4.6

gMVP

0.43

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over