rs876661285

Positions:

• chr13-32396981-TA-T

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.9588delA​(p.Asp3197fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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: 33)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 2.83

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 (HGNC:):

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 13-32396981-TA-T is Pathogenic according to our data. Variant chr13-32396981-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 234902.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9588delA	p.Asp3197fs	frameshift_variant	26/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9588delA	p.Asp3197fs	frameshift_variant	26/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9219delA	p.Asp3074fs	frameshift_variant	26/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1646delA		non_coding_transcript_exon_variant	25/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1646delA		3_prime_UTR_variant	25/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, reviewed by expert panel

curation

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Dec 15, 2017

Variant allele predicted to encode a truncated non-functional protein. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2016

This deletion of one nucleotide in BRCA2 is denoted c.9588delA at the cDNA level and p.Asp3197ThrfsX20 (D3197TfsX20) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 9816delA. The normal sequence, with the base that is deleted in braces, is CTAA[A]GACT. The deletion causes a frameshift which changes an Aspartic Acid to a Threonine at codon 3197, and creates a premature stop codon at position 20 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through protein truncation. Based on the currently available information, we consider this deletion to be a likely pathogenic variant. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 22, 2020

This variant deletes 1 nucleotide in exon 26 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9816delA in Breast Cancer Information Core (BIC) nomenclature. This variant is expected to result in a defective protein product. While this variant is not predicted to trigger nonsense-mediated decay, it causes the partial loss of the RAD51 binding domain (PMID: 9126738, 9192668) and the nuclear localization signals. Multiple functional studies using murine cells found that similar Brca2 truncation impaired function in and regulation of homology-mediated and high fidelity DNA repair and replication fork protection (PMID: 9699678, 11239455, 11532935, 15800615, 16997331, 21565612). Mice harboring Brca2 variant lacking the last exon also have increased tumor incidence and decreased survival compared to littermates (PMID: 11861370). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

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: rs876661285; hg19: chr13-32971118;