rs397509181

chr17-43076486-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PM2 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):c.4484+1del variant causes a splice donor 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 Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 splice_donor
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 3.88

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 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.02253219 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.9, offset of 0 (no position change), new splice context is: aaaGTaaga. Cryptic site results in inframe 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-43076486-AC-A is Pathogenic according to our data. Variant chr17-43076486-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 55211.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43076486-AC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4484+1del		splice_donor_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4484+1del		splice_donor_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:5

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, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 31, 2019	The BRCA1 c.4484+1delG variant is classified as Pathogenic (PVS1, PM2, PP5) The BRCA1 c.4484+1delG variant is located in a splice donor region. Computational predictions support a deleterious effect on splicing and a likely disruption of the protein reading frame and non-sense mediated decay of the resulting protein product (PVS1).This variant is absent from population databases (PM2). not in population databases ENIGMA/Parsons 2019 co-segregation in ICON data from 1 family The variant has been reported in dbSNP (rs397509181) and in the HGMD database: CD004791. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 55211). Multifactorial analysis by ENIGMA consortium confirms this variant as pathogenic -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.996657 -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variant is a single base pair deletion in the first base of intron 13 of the BRCA1 gene. This position is conserved in the human and other genomes and might be involved in mRNA processing. Therefore, this variant is expected to disrupt RNA splicing and results in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This variant has been reported in the literature in Turkish breast/ovarian families (PMID: 10952777). The mutation database ClinVar contains entries for this variant (Variation ID: 55211). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 26, 2019	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. 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). This variant has been observed in an individual with a personal and family history of breast and/or ovarian cancer (PMID: 10952777). This variant is also known as IVS-14+1delG in the literature. ClinVar contains an entry for this variant (Variation ID: 55211). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 13 of the BRCA1 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)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 3
DS_DL_spliceai		0.97		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397509181; hg19: chr17-41228503;