13-32319134-A-G

Variant names:

• chr13-32319134-A-G
• rs4987046
• ENST00000530893:c.-245A>G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001406722.1(BRCA2):​c.-245A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,613,770 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (10 hom.)
• Consequence: BRCA2 NM_001406722.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel U:2 B:38 O:2
• Conservation: PhyloP100: 0.845

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009805024).
• BP6: Variant 13-32319134-A-G is Benign according to our data. Variant chr13-32319134-A-G is described in ClinVar as [Benign]. Clinvar id is 37734.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32319134-A-G is described in Lovd as [Benign]. Variant chr13-32319134-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.125A>G	p.Tyr42Cys	missense_variant	Exon 3 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000530893	c.-245A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 27	1		ENSP00000499438.2
BRCA2	ENST00000380152.8	c.125A>G	p.Tyr42Cys	missense_variant	Exon 3 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893	c.-245A>G		5_prime_UTR_variant	Exon 3 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.125A>G		non_coding_transcript_exon_variant	Exon 2 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 232 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00163 AC: 409 AN: 251278 Hom.: 0 AF XY: 0.00169 AC XY: 229 AN XY: 135850

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00213 AC: 3109 AN: 1461456 Hom.: 10 Cov.: 32 AF XY: 0.00215 AC XY: 1563 AN XY: 727048

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00238

Gnomad4 FIN exome AF: 0.00251

Gnomad4 NFE exome AF: 0.00227

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.00145 AC XY: 108 AN XY: 74484

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00248

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00140

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00169 AC: 205

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00196

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:38 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:12 Other:1

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

-

Breast Cancer Information Core (BIC) (BRCA2)

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

May 24, 2016

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Oct 30, 2014

Pathway Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 = 1.22E-18. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.04021 (Asian), 0.1016 (African), 0.04749 (European), derived from 1000 genomes (2012-04-30). -

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:10 Other:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 19, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

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

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 28, 2013

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. -

May 25, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

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

- -

not provided Uncertain:1 Benign:4

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP1, BP4, BS1, BS2 -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Nov 25, 2014

Color Diagnostics, LLC DBA Color Health

Significance: 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. -

Oct 10, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 16, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary breast ovarian cancer syndrome Benign:4

Oct 09, 2013

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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

- -

Familial cancer of breast Benign:2

Feb 23, 2017

Baylor Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group D1 Uncertain:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Breast and/or ovarian cancer Benign:1

Apr 14, 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 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.6
DANN	Benign	0.49
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.93
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.0098	T;T
MetaSVM	Benign	-0.76	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.089
Sift	Benign	0.11	T;T
Sift4G	Benign	0.11	T;T
Vest4		0.31
MVP		0.78
MPC		0.023
ClinPred		0.0018	T
GERP RS		0.28
gMVP		0.40

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

Other links and lift over

dbSNP: rs4987046; hg19: chr13-32893271; COSMIC: COSV104701240; COSMIC: COSV104701240;