17-43074328-TACCTAGATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAAATCGTGTGGCCCAGACTCTTCCAGCTGTTGCTCCTCCACATCAACAACCTTAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCTGAAGACTCCCAGAGCAACTGTGCATGTACCACCTATCATCTAATGATGGGCATTTAGAAGGGGATG-T

Position:

• chr17-43074328-TACCTAGATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAAATCGTGTGGCCCAGACTCTTCCAGCTGTTGCTCCTCCACATCAACAACCTTAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCTGAAGACTCCCAGAGCAACTGTGCATGTACCACCTATCATCTAATGATGGGCATTTAGAAGGGGATG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The ENST00000591534.5(BRCA1):​c.-41_148+2del​(p.Met1_Glu50del) variant causes a start lost, conservative inframe deletion, splice region 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 ENST00000591534.5 start_lost, conservative_inframe_deletion, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.00

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.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000591534.5.
• PP5: Variant 17-43074328-TACCTAGATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAAATCGTGTGGCCCAGACTCTTCCAGCTGTTGCTCCTCCACATCAACAACCTTAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCTGAAGACTCCCAGAGCAACTGTGCATGTACCACCTATCATCTAATGATGGGCATTTAGAAGGGGATG-T is Pathogenic according to our data. Variant chr17-43074328-TACCTAGATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAAATCGTGTGGCCCAGACTCTTCCAGCTGTTGCTCCTCCACATCAACAACCTTAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCTGAAGACTCCCAGAGCAACTGTGCATGTACCACCTATCATCTAATGATGGGCATTTAGAAGGGGATG-T is described in ClinVar as [Pathogenic]. Clinvar id is 433739.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-43074328-TACCTAGATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAAATCGTGTGGCCCAGACTCTTCCAGCTGTTGCTCCTCCACATCAACAACCTTAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCTGAAGACTCCCAGAGCAACTGTGCATGTACCACCTATCATCTAATGATGGGCATTTAGAAGGGGATG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4487_4675+2del	p.Ser1496_Glu1559delinsTer	stop_gained, splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	14/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4487_4675+2del	p.Ser1496_Glu1559delinsTer	stop_gained, splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	14/23	1	NM_007294.4	ENSP00000350283.3

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

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

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: rs1555581778; hg19: chr17-41226345;