13-32346707-T-C

Variant names:

• chr13-32346707-T-C
• rs206080
• NM_000059.4:c.6938-120T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000059.4(BRCA2):​c.6938-120T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 690,196 control chromosomes in the GnomAD database, including 340,509 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72918 hom., cov: 32)
  • Exomes 𝑓: 1.0 (267591 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: -2.18
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 13-32346707-T-C is Benign according to our data. Variant chr13-32346707-T-C is described in ClinVar as Benign. ClinVar VariationId is 209939.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6938-120T>C		intron_variant	Intron 12 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6938-120T>C		intron_variant	Intron 12 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6569-120T>C		intron_variant	Intron 12 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6938-120T>C		intron_variant	Intron 11 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.979 AC: 148752 AN: 152008 Hom.: 72868 Cov.: 32

Gnomad AFR AF: 0.926

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.978

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.985

GnomAD4 exome AF: 0.997 AC: 536588 AN: 538070 Hom.: 267591 AF XY: 0.997 AC XY: 283208 AN XY: 283942

African (AFR) AF: 0.927 AC: 12703 AN: 13704

American (AMR) AF: 0.995 AC: 17608 AN: 17704

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 15230 AN: 15230

East Asian (EAS) AF: 1.00 AC: 30528 AN: 30528

South Asian (SAS) AF: 0.998 AC: 42676 AN: 42766

European-Finnish (FIN) AF: 1.00 AC: 32591 AN: 32592

Middle Eastern (MID) AF: 0.991 AC: 2121 AN: 2140

European-Non Finnish (NFE) AF: 1.00 AC: 354793 AN: 354910

Other (OTH) AF: 0.994 AC: 28338 AN: 28496

GnomAD4 genome AF: 0.979 AC: 148860 AN: 152126 Hom.: 72918 Cov.: 32 AF XY: 0.979 AC XY: 72807 AN XY: 74354

African (AFR) AF: 0.926 AC: 38426 AN: 41506

American (AMR) AF: 0.992 AC: 15178 AN: 15294

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5187 AN: 5188

South Asian (SAS) AF: 0.998 AC: 4813 AN: 4822

European-Finnish (FIN) AF: 1.00 AC: 10606 AN: 10606

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67903 AN: 67924

Other (OTH) AF: 0.985 AC: 2078 AN: 2110

Alfa AF: 0.990 Hom.: 3847

Bravo AF: 0.976

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 01, 2017

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:2

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 0.8902 (African), derived from 1000 genomes (2012-04-30).

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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	-0.91
CADD	Benign	0.17
DANN	Benign	0.41
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs206080; hg19: chr13-32920844;