rs80359732

Variant names:

• chr13-32379495-CA-C
• rs80359732
• NM_000059.4:c.8940delA

Your query was ambiguous. Multiple possible variants found:

• chr13-32379495-CA-C
• chr13-32379495-CA-CAA

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.8940delA​(p.Glu2981LysfsTer7) 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: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 1.16

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 13-32379495-CA-C is Pathogenic according to our data. Variant chr13-32379495-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 418600.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379495-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32379495-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32379495-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32379495-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8940delA	p.Glu2981LysfsTer7	frameshift_variant	Exon 22 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8940delA	p.Glu2981LysfsTer7	frameshift_variant	Exon 22 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8571delA	p.Glu2858LysfsTer7	frameshift_variant	Exon 22 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*998delA		non_coding_transcript_exon_variant	Exon 21 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*998delA		3_prime_UTR_variant	Exon 21 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

-

University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2017

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Hereditary breast ovarian cancer syndrome Pathogenic:2

Aug 22, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). A different variant (c.8941delG) giving rise to the same protein effect observed here (p.Glu2981Lysfs*7) has been reported in an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 24156927). This variant has been observed in an individual affected with breast cancer (PMID: 26824983). This variant is also known as c.8934delA in the literature. ClinVar contains an entry for this variant (Variation ID: 418600). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu2981Lysfs*7) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. -

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1

Nov 02, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This deletion of one nucleotide in BRCA2 is denoted c.8940delA at the cDNA level and p.Glu2981LysfsX7 (E2981KfsX7) at the protein level. The normal sequence, with the base that is deleted in braces, is CAAAAAA[A]GAAA. The deletion causes a frameshift which changes a Glutamic Acid to a Lysine at codon 2981, and creates a premature stop codon at position 7 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.8940delA, also defined as c.8934delA or 9168delA by alternate nomenclature, has been reported in at least one patient with breast cancer (Lin 2016). We consider this variant to be pathogenic. -

Familial cancer of breast Pathogenic:1

-

Department of Medical Genetics, Istanbul Demiroglu Bilim University Medical School

Significance: Pathogenic

Review Status: no assertion criteria provided

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: rs80359732; hg19: chr13-32953632;