rs876659770

chr13-32355061-CCAAA-CGG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):c.7209_7212delinsGG(p.Lys2404GlyfsTer7) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T2403T) has been classified as Likely benign. 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:5
• Conservation: PhyloP100: 6.34

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32355062-CAAA-GG is Pathogenic according to our data. Variant chr13-32355062-CAAA-GG is described in ClinVar as [Pathogenic]. Clinvar id is 232446.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7209_7212delinsGG	p.Lys2404GlyfsTer7	frameshift_variant	14/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7209_7212delinsGG	p.Lys2404GlyfsTer7	frameshift_variant	14/27	5	NM_000059.4	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:5

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2015

The c.7209_7212delCAAAinsGG pathogenic mutation (also known as 7437delCAAAinsGG), located in coding exon 13 of the BRCA2 gene, results from the deletion of 4 nucleotides and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in a high-risk breast and/or ovarian cancer patient in Austria (Tea MK et al. Maturitas. 2014 Jan;77(1):68-72).In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneKor MSA

Jan 01, 2020

This sequence change deletes 4 nucleotides and inserts 2 other nucleotides in exon 14 of the BRCA2 mRNA. This creates a premature translational stop signal 7 amino acid residues later and is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has been described in the international literature in an individual with a personal and/or family history of breast cancer and/or ovarian cancer (PMID: 24156927) and in an individual undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 232446). -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 06, 2018

This sequence change creates a premature translational stop signal (p.Lys2404Glyfs*7) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with a personal and/or family history of breast cancer and/or ovarian cancer (PMID: 24156927). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been 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: rs876659770; hg19: chr13-32929199;