13-32319060-AT-ATT

Position:

• chr13-32319060-AT-ATT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000059.4(BRCA2):​c.68-7dup variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,568,270 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: BRCA2 NM_000059.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.675

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 -8 ACMG points.

• BP6: Variant 13-32319060-A-AT is Benign according to our data. Variant chr13-32319060-A-AT is described in ClinVar as [Likely_benign]. Clinvar id is 38065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.68-7dup		splice_polypyrimidine_tract_variant, intron_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.68-7dup		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.000399 AC: 60 AN: 150506 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000266

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000119

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000280 AC: 397 AN: 1417648 Hom.: 1 Cov.: 32 AF XY: 0.000264 AC XY: 186 AN XY: 705250

Gnomad4 AFR exome AF: 0.00127

Gnomad4 AMR exome AF: 0.000328

Gnomad4 ASJ exome AF: 0.0000793

Gnomad4 EAS exome AF: 0.000182

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.0000391

Gnomad4 NFE exome AF: 0.000228

Gnomad4 OTH exome AF: 0.000531

GnomAD4 genome AF: 0.000405 AC: 61 AN: 150622 Hom.: 0 Cov.: 33 AF XY: 0.000408 AC XY: 30 AN XY: 73566

Gnomad4 AFR AF: 0.00114

Gnomad4 AMR AF: 0.000265

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000418

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000119

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000423

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2016	Variant summary: The BRCA2 c.68-7dupT variant involves an insertion of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 118368 control chromosomes. This variant has been observed to co-occur with another potentially pathogenic variant in BRCA1 (Press_2008) and BRCA2 c.1813dup/p.Ile605AsnfsX11 (UMD) and c.1949_1950delTA/p.Ile650LysfsX22 (Diez_2011). One internal sample also carried a pathogenic BRCA1 variant c.5387C>A/p.Ser1796X. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	BRCA2: BP4 -

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:3

Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 03, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Feb 11, 2015	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 11, 2016	- -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 02, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 12, 2022

- -

BRCA2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2019

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). -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

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: rs276174878; hg19: chr13-32893197;