rs878853285

chr17-43051118-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):c.5278-2del variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 splice_acceptor
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 4.29

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [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 9.2, offset of 8, new splice context is: tctcttcttccgatcttcAGggg. 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 17-43051118-CT-C is Pathogenic according to our data. Variant chr17-43051118-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 236262.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43051118-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43051118-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5278-2del		splice_acceptor_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5278-2del		splice_acceptor_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3

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, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 03, 2016	Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.5278_5332del and r.5278_5285del transcripts (encoding predicted non-functional proteins). -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 17, 2020

This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 19 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been observed in several individuals with a personal or family history of breast or ovarian cancer (PMID: 23451180, 30430080). This variant is also known as IVS20-2delA in the literature. ClinVar contains an entry for this variant (Variation ID: 236262). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 23451180). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.79		Position offset: -9
DS_AL_spliceai		0.96		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853285; hg19: chr17-41203135;