NM_000059.4:c.9257-16T>C

Variant names:

• chr13-32394673-T-C
• rs11571818
• NM_000059.4:c.9257-16T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000059.4(BRCA2):​c.9257-16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00788 in 1,609,366 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (69 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:26
• Conservation: PhyloP100: 0.00

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 13-32394673-T-C is Benign according to our data. Variant chr13-32394673-T-C is described in ClinVar as [Benign]. Clinvar id is 52790.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32394673-T-C is described in Lovd as [Benign]. Variant chr13-32394673-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00601 (915/152358) while in subpopulation NFE AF= 0.0085 (578/68034). AF 95% confidence interval is 0.00792. There are 3 homozygotes in gnomad4. There are 437 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9257-16T>C		intron_variant	Intron 24 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9257-16T>C		intron_variant	Intron 24 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8888-16T>C		intron_variant	Intron 24 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1315-16T>C		intron_variant	Intron 23 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00602 AC: 916 AN: 152240 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00849

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00659 AC: 1610 AN: 244488 Hom.: 15 AF XY: 0.00687 AC XY: 910 AN XY: 132364

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00265

Gnomad ASJ exome AF: 0.00403

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00692

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.00901

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00807 AC: 11761 AN: 1457008 Hom.: 69 Cov.: 31 AF XY: 0.00823 AC XY: 5961 AN XY: 724638

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00265

Gnomad4 ASJ exome AF: 0.00449

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00647

Gnomad4 FIN exome AF: 0.00974

Gnomad4 NFE exome AF: 0.00896

Gnomad4 OTH exome AF: 0.00723

GnomAD4 genome AF: 0.00601 AC: 915 AN: 152358 Hom.: 3 Cov.: 33 AF XY: 0.00587 AC XY: 437 AN XY: 74506

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.00850

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00596 Hom.: 0

Bravo AF: 0.00539

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:26

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:9

Apr 10, 2014

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 22, 2016

Fulgent Genetics, Fulgent Genetics

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

- -

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

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

- -

-

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

- -

Jan 12, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.01055 (European), derived from 1000 genomes (2012-04-30). -

not specified Benign:7

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

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 c.9257-16T>C variant was identified in 121 of 53524 proband chromosomes (frequency: 0.002) from individuals or families with Breast and Ovarian cancer, and was present in 4 of 530 control chromosomes (frequency: 0.08) from healthy individuals (Caputo 2011, Borg 2010, Hadijisavvas 2003, Cvok 2008, Diez 2003). The variant was identified in dbSNP (ID: rs11571818) with “other” allele, with a minor allele frequency of 0.0044(1000 Genomes Project); in NHLBI Exome Sequencing Project (Exome Variant Server) in 67 of 8600 European and 10 of 4406 African Americans; in Exome Aggregation Consortium (ExAC) database in 574(3 homozygote) of 56204 of Europeans(non-Finnish), in 15 of 9522 Africans, in 25 of 10298 Latinos, in 116 (4 homozygote) of 15288 South Asians , in 77 (2 homozygote) of 6222 Europeans (Finnish) and 5 of 820 other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also found in LOVD, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports, classified as benign by Invitae, as benign by Counsyl, as benign by GeneDX, as benign by Emory Genetics, as Likely benign by CHEO and as uncertain significance by BIC). It was also identified in GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (1X, classified as “likely benign” by a clinical laboratory), the BIC database (12X with no clinical importance), and UMD (73X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1:c.5116G>A (p.Gly1706Arg), c.4391delC (p.Pro1464LeufsX2), c.81_134delp.Cys27X); BRCA2:c.6275_6276delTT (p.Leu2092ProfsX7), c.4889C>G (p.Ser1630X), increasing the likelihood that the c.9257-16T>C variant does not have clinical significance. The c.9257-16T>C 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 splicing studies (Bonnet 2008, Claes 2003) showed that the c.9257-16T>C do not result in aberrant splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

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

- -

Oct 13, 2015

Eurofins Ntd Llc (ga)

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

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Apr 19, 2022

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

- -

Feb 03, 2014

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cancer of breast Benign:2

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2017

Baylor Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Dec 09, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 15, 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. -

Breast and/or ovarian cancer Benign:1

Apr 28, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.32

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: rs11571818; hg19: chr13-32968810; COSMIC: COSV104701316; COSMIC: COSV104701316;