rs276174915

chr13-32379506-AAAGATTCAGGT-A

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.8948_8953+5del variant causes a splice donor, coding sequence change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 splice_donor, coding_sequence
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.68

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.9, offset of -7, new splice context is: aaaGTatgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32379506-AAAGATTCAGGT-A is Pathogenic according to our data. Variant chr13-32379506-AAAGATTCAGGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 141449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32379506-AAAGATTCAGGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8948_8953+5del		splice_donor_variant, coding_sequence_variant	22/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8948_8953+5del		splice_donor_variant, coding_sequence_variant	22/27	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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2015	This variant is denoted BRCA2 c.8948_8953+5del11 and consists of a deletion of 11 nucleotides at the exon/intron boundary of exon 22. The normal sequence, with the bases that are deleted in braces, is AAAG[del11]tatg where the capital letters are exonic and the lower case are intronic. This variant, also known as BRCA2 c.8948_8953+5del using alternate nomenclature, destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Functional studies using a minigene assay have demonstrated that this variant causes aberrant splicing (Acedo 2014). Based on the currently available information, we consider BRCA2 c.8948_8953+5del11 to be a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 17, 2023	The BRCA2 c.8948_8953+5del (p.Asp2983_Ser2984del) variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. This variant has been reported in the published literature in an experimental study that supports this variant impacts BRCA2 mRNA splicing (PMID: 25382762 (2015)). Additionally, the variant has been reported in families with increased risk for breast and/or ovarian cancer (PMIDs: 29446198 (2019), 28150238 (2017)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 14, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25382762). ClinVar contains an entry for this variant (Variation ID: 141449). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 22 (c.8948_8953+5del) of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2022	Variant summary: BRCA2 c.8948_8953+5del11 is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5 splicing donor site. Four predict the variant creates a cryptic 5 donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Acedo_2015). The variant was absent in 248098 control chromosomes (gnomAD). c.8948_8953+5del11 has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (LaDuca_2017, Rebbeck_2018). These data indicate that the variant may be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Oct 02, 2015

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2020

The c.8948_8953+5del11 intronic variant (also known as 9176del11), results from a deletion of 11 nucleotides between positions 8948 and 8953+5, which involves the canonical splice site after coding exon 21 of the BRCA2 gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Further, this alteration has been shown to result in aberrant splicing, using a minigene assay (Acedo A et al. Hum. Mutat., 2015 Feb;36:210-21). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). In addition to the clinical data presented in the literature, 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 a disease-causing mutation. -

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: rs276174915; hg19: chr13-32953643;