rs1555594718

Positions:

• chr17-43099609-GGAACTGCGTCTTTTACATTTTTTATAACTCACCATAGGGCTCATAAAATTCACTTCCCAAAGCTGCCTACCACAAATACAAATTATGACCAAGATTTTTGGCAAAACTATAAGATAAGGAATCCAGCAATTATTATTAAATACTTAAAAAACCTGAGACCCTTACCCAATTCAATGT-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_007294.4(BRCA1):​c.536_547+165del 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 (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.704

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 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 17-43099609-GGAACTGCGTCTTTTACATTTTTTATAACTCACCATAGGGCTCATAAAATTCACTTCCCAAAGCTGCCTACCACAAATACAAATTATGACCAAGATTTTTGGCAAAACTATAAGATAAGGAATCCAGCAATTATTATTAAATACTTAAAAAACCTGAGACCCTTACCCAATTCAATGT-G is Pathogenic according to our data. Variant chr17-43099609-GGAACTGCGTCTTTTACATTTTTTATAACTCACCATAGGGCTCATAAAATTCACTTCCCAAAGCTGCCTACCACAAATACAAATTATGACCAAGATTTTTGGCAAAACTATAAGATAAGGAATCCAGCAATTATTATTAAATACTTAAAAAACCTGAGACCCTTACCCAATTCAATGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 531432.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.536_547+165del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	7/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.536_547+165del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	7/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2019

This variant is a deletion of the genomic region encompassing part of exon 7 (c.536_547+165del) of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 531432). 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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555594718; hg19: chr17-41251626;