rs876659229

Positions:

• chr13-32356422-TGATA-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.7436-2_7437delAGAT​(p.Asp2479fs) variant causes a frameshift, splice acceptor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA2 NM_000059.4 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.68

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 13-32356422-TGATA-T is Pathogenic according to our data. Variant chr13-32356422-TGATA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 231567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32356422-TGATA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7436-2_7437delAGAT	p.Asp2479fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	15/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7436-2_7437delAGAT	p.Asp2479fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	15/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7067-2_7068delAGAT	p.Asp2356fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	15/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7436-2_7437delAGAT		splice_acceptor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	14/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2024

The c.7436-2_7437delAGAT variant, located in the BRCA2 gene, is caused by the deletion of the first two nucleotides of coding exon 14 as well as the first two nucleotides upstream of this coding exon, causing a disruption of the canonical acceptor splice site. This alteration has been identified in one family whose clinical history was suggestive of hereditary breast and ovarian cancer (van Harssel JJ et al. Fam Cancer. 2010 Jun;9(2):193-201). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide region is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 16, 2023

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 08, 2020

Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant, also known as "c.7436_7437-2delAGAT" in the literature, has been reported in a family affected with breast and/or ovarian cancer (PMID: 19949876). ClinVar contains an entry for this variant (Variation ID: 231567). This variant is a deletion of the genomic region encompassing part of intron 14 and part of exon 15 (c.7436-2_7437del) of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.95		Position offset: 19
DS_AL_spliceai		0.95		Position offset: 6

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

Publications

LitVar

Other links and lift over

dbSNP: rs876659229; hg19: chr13-32930559;