chr13-32333398-C-CT

Variant names:

• chr13-32333398-C-CT
• rs276174816
• NM_000059.4:c.1909+22dupT

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_000059.4(BRCA2):​c.1909+22dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0323 in 916,340 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.032 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: 0.591

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 -12 ACMG points.

• BP6: Variant 13-32333398-C-CT is Benign according to our data. Variant chr13-32333398-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 220876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0323 (29585/916340) while in subpopulation NFE AF= 0.0333 (23413/702962). AF 95% confidence interval is 0.0329. There are 1 homozygotes in gnomad4_exome. There are 14191 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1909+22dupT		intron_variant	Intron 10 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1909+11_1909+12insT		intron_variant	Intron 10 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.1540+11_1540+12insT		intron_variant	Intron 10 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1909+11_1909+12insT		intron_variant	Intron 9 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 147 AN: 146112 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.000575

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000479

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00199

Gnomad SAS AF: 0.000645

Gnomad FIN AF: 0.000758

Gnomad MID AF: 0.00662

Gnomad NFE AF: 0.00139

Gnomad OTH AF: 0.00150

GnomAD4 exome AF: 0.0323 AC: 29585 AN: 916340 Hom.: 1 Cov.: 29 AF XY: 0.0313 AC XY: 14191 AN XY: 453344

Gnomad4 AFR exome AF: 0.0317

Gnomad4 AMR exome AF: 0.0320

Gnomad4 ASJ exome AF: 0.0335

Gnomad4 EAS exome AF: 0.0265

Gnomad4 SAS exome AF: 0.0282

Gnomad4 FIN exome AF: 0.0223

Gnomad4 NFE exome AF: 0.0333

Gnomad4 OTH exome AF: 0.0320

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00101 AC: 147 AN: 146168 Hom.: 0 Cov.: 32 AF XY: 0.000957 AC XY: 68 AN XY: 71052

Gnomad4 AFR AF: 0.000574

Gnomad4 AMR AF: 0.000479

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00200

Gnomad4 SAS AF: 0.000862

Gnomad4 FIN AF: 0.000758

Gnomad4 NFE AF: 0.00139

Gnomad4 OTH AF: 0.00149

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

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.1909+22dupT variant was identified in a study by Théry (2011) in at least one family undergoing genetic counseling. The variant was also identified in the LOVD, and the UMD (6X as an unclassified variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.135_441dup (p.Gln148IlefsX20)), increasing the likelihood that the c.1909+22dup variant does not have clinical significance. The variant occurs outside of the splicing consensus sequence, but is within a polyT tract which can sometimes cause alternative splicing. Thery (2011) used a functional minigene-based splicing assay and found no effect of the variant on splicing. In addition, five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Hereditary cancer-predisposing syndrome Benign:2

Mar 18, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Breast and/or ovarian cancer Benign:1

Nov 04, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Benign:1

Mar 03, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs276174816; hg19: chr13-32907535;