rs1555599292

Positions:

• chr17-43115779-ACTAGC-ATCAAGGT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_007294.4(BRCA1):​c.81-5_81-1delinsACCTTGA variant causes a splice acceptor, splice polypyrimidine tract, 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 splice_acceptor, splice_polypyrimidine_tract, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.52

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.009477826 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43115780-CTAGC-TCAAGGT is Pathogenic according to our data. Variant chr17-43115780-CTAGC-TCAAGGT is described in ClinVar as [Pathogenic]. Clinvar id is 491192.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.81-5_81-1delinsACCTTGA		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.81-5_81-1delinsACCTTGA		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_007294.4	P4

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 17, 2020

This variant causes a substitution of the last 5 nucleotides in intron 2 of the BRCA1 gene. This variant may also be described as IVS2-5delGCTAGinsACCTTGA or IVS2-5del5ins7. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast cancer (Color internal data). Multiple other variants impacting canonical splice site nucleotides (-2 and -1 positions) in the intron 2 splice acceptor site have been reported as disease-causing in ClinVar (variation ID: 55715, 55716, 55717, 91668, 136092) and observed in individuals affected with breast and/or ovarian cancer (PMID: 22711857, 30078507, 30287823, 32438681; UMD database). The other canonical splice acceptor site variants in intron 2 also have been shown to be defective in haploid cell growth assays (PMID: 30209399, 31467430) and c.81-1G>C has been shown to disrupt splicing leading to an absent or nonfunctional protein product (PMID: 22505045, 23239986). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

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: rs1555599292; hg19: chr17-41267797;