Variant 13-32356588-CTCTGCGTGTTCTCATAAACAGGTATGTGTTTGTCTACAATACTGATGGCTTTTATGACAGAGTGTAATTTTATTTCATTAACTAGTATCTACAAATGGCTTTGTTTAAAGAATGAACACATTAGTGCAGGAATGGATGAATGAAATCATCATATTTTCTAATTAGCCTGCAGTGGCAGCCTCTGGCCCCTTGCTAGGCCTGCCTCATCCTGCTAAAGTGATCTGTGCTTCCAAATTACTACTTCTTTTCCCCCTTCAAATCTTTCTTATTTTGTCATTGTAAA-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000059.4(BRCA2):c.7598_7617+263del variant causes a splice donor, splice donor 5th base, coding sequence, intron 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 (★). Synonymous variant affecting the same amino acid position (i.e. S2533S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

BRCA2
NM_000059.4 splice_donor, splice_donor_5th_base, coding_sequence, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.54

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-32356588-CTCTGCGTGTTCTCATAAACAGGTATGTGTTTGTCTACAATACTGATGGCTTTTATGACAGAGTGTAATTTTATTTCATTAACTAGTATCTACAAATGGCTTTGTTTAAAGAATGAACACATTAGTGCAGGAATGGATGAATGAAATCATCATATTTTCTAATTAGCCTGCAGTGGCAGCCTCTGGCCCCTTGCTAGGCCTGCCTCATCCTGCTAAAGTGATCTGTGCTTCCAAATTACTACTTCTTTTCCCCCTTCAAATCTTTCTTATTTTGTCATTGTAAA-C is Pathogenic according to our data. Variant chr13-32356588-CTCTGCGTGTTCTCATAAACAGGTATGTGTTTGTCTACAATACTGATGGCTTTTATGACAGAGTGTAATTTTATTTCATTAACTAGTATCTACAAATGGCTTTGTTTAAAGAATGAACACATTAGTGCAGGAATGGATGAATGAAATCATCATATTTTCTAATTAGCCTGCAGTGGCAGCCTCTGGCCCCTTGCTAGGCCTGCCTCATCCTGCTAAAGTGATCTGTGCTTCCAAATTACTACTTCTTTTCCCCCTTCAAATCTTTCTTATTTTGTCATTGTAAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 254094.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7598_7617+263del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	15/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.7598_7617+263del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	15/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 25, 2016

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in BRCA2 are known to be pathogenic (PMID: 20104584). This sequence change deletes 283 nucleotides from exon 15 of the BRCA2 mRNA (c.7598_7617+263del), causing a frameshift at codon 2534. This creates a premature translational stop signal 6 positions downstream and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.