rs80359303

Positions:

• chr13-32333238-CAAATA-C
• chr13-32333238-CAAATA-CA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.1762_1766del​(p.Asn588ValfsTer7) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 5.39

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32333238-CAAATA-C is Pathogenic according to our data. Variant chr13-32333238-CAAATA-C is described in ClinVar as [Pathogenic]. Clinvar id is 266657.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32333238-CAAATA-C is described in Lovd as [Pathogenic]. Variant chr13-32333238-CAAATA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1762_1766del	p.Asn588ValfsTer7	frameshift_variant	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1762_1766del	p.Asn588ValfsTer7	frameshift_variant	10/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Oct 18, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2020	This sequence change deletes 5 nucleotides from exon 10 of the BRCA2 mRNA (c.1762_1766delAATAA), causing a frameshift at codon 588. This creates a premature translational stop signal (p.Asn588Valfs*7) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2020	Variant summary: BRCA2 c.1762_1766delAATAA (p.Asn588ValfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249630 control chromosomes. c.1762_1766delAATAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories, one consortium (CIMBA) and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2018

The c.1762_1766delAATAA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 1762 to 1766, causing a translational frameshift with a predicted alternate stop codon (p.N588Vfs*7). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Jul 28, 2023

The variant BRCA2:c.1762_1766del, p.(Asn588Valfs*7), which is located in the coding exon 10 of the BRCA2 gene, results from a deletion of 5 residues at nucleotide position c.1762-1766. The variant causes a frameshift that results in the replace of an asparagine residue by a valine at protein position 588, followed by a premature translation stop codon after seven amino acids. The variant affects and exon (10/27) that is present in biologically relevant transcripts and it is predicted to cause protein truncation/absent due to non-sense mediated decay in a gene where loss of function is a known mechanism of disease. The variant is classified as very rare in the overall population (no carriers in gnomAD, v4.1.0). The variant has already been described as Pathogenic in three independent families (PMID: 29446198), and has been classified as Pathogenic in five entries in ClinVar (ClinVar ID 266657). In addition, the variant has been classified as Pathogenic by a panel of experts (ENIGMA Consortium). In summary, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80359303; hg19: chr13-32907375;