rs781354453

chr13-32319060-AT-Achr13-32319060-A-AT

Variant summary

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

The NM_000059.4(BRCA2):c.68-7del 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 0.000262 in 1,562,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: BRCA2 NM_000059.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign reviewed by expert panel U:4 B:6
• 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-AT-A is Benign according to our data. Variant chr13-32319060-AT-A is described in ClinVar as [Benign]. Clinvar id is 52188.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32319060-AT-A is described in Lovd as [Benign]. Variant chr13-32319060-AT-A is described in Lovd as [Likely_benign]. Variant chr13-32319060-AT-A is described in Lovd as [Benign].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000465 AC: 7 AN: 150484 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000974

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000593

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000285 AC: 402 AN: 1412396 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 208 AN XY: 702480

Gnomad4 AFR exome AF: 0.000341

Gnomad4 AMR exome AF: 0.000944

Gnomad4 ASJ exome AF: 0.000239

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.000631

Gnomad4 FIN exome AF: 0.000275

Gnomad4 NFE exome AF: 0.000243

Gnomad4 OTH exome AF: 0.000258

GnomAD4 genome AF: 0.0000465 AC: 7 AN: 150600 Hom.: 0 Cov.: 33 AF XY: 0.0000408 AC XY: 3 AN XY: 73556

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000974

Gnomad4 NFE AF: 0.0000593

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00521 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 16, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	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. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

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

Benign, reviewed by expert panel	curation	ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	Oct 10, 2023	The c.68-7del variant is an intronic variant occurring in intron 2 of the BRCA2 gene. The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.00002293 in the Latino/Admixed American population which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to <= 0.0001) for BS1_Supporting (BS1_Supporting met). This BRCA2 intronic variant is outside of the native donor and acceptor 1,2 splice sites, and SpliceAI predictor score of 0.04 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is an intronic variant, and mRNA experimental analysis indicates no impact on splicing (PMIDs: 10534775, 21673748, 22505045), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 35979650) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.32 (based on Pathology LR=0.32), within the thresholds for Supporting benign evidence (LR 0.23-0.48) (BP5 met; PMID: 35979650). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1_Supporting, BP4, BP7_Strong (RNA), BS3, BP5). -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 15, 2019

This variant is associated with the following publications: (PMID: 10023017, 10451700, 17333343, 10534775) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;