rs80357647

Positions:

• chr17-43092436-CTAATGTTATTA-C

Variant summary

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

The ENST00000357654.9(BRCA1):​c.3084_3094del​(p.Asn1029ArgfsTer5) variant causes a frameshift 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. R1028R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 ENST00000357654.9 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 1.25

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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43092436-CTAATGTTATTA-C is Pathogenic according to our data. Variant chr17-43092436-CTAATGTTATTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 54768.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092436-CTAATGTTATTA-C is described in Lovd as [Pathogenic]. Variant chr17-43092436-CTAATGTTATTA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3084_3094del	p.Asn1029ArgfsTer5	frameshift_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.3084_3094del	p.Asn1029ArgfsTer5	frameshift_variant	10/23	1	NM_007294.4	ENSP00000350283	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:15

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6

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	Breast Cancer Information Core (BIC) (BRCA1)	Aug 31, 1999	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 18, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jan 12, 2015	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3203_3213del11; This variant is associated with the following publications: (PMID: 16267036, 23199084, 24312913, 17574839, 11334729, 11720839, 12481264, 25452441, 29339979, 35216584, 34981296) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 10, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 02, 2021	Variant summary: BRCA1 c.3084_3094del11 (p.Asn1029ArgfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251142 control chromosomes and c.3084_3094del11 has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Moller_2001, Judkins_2005, Couch_2015, Grindedal_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed this variant after 2014, including one expert panel and one consortium: all submitters have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 19, 2023	ClinVar contains an entry for this variant (Variation ID: 54768). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and triple-negative breast cancer (PMID: 17574839, 23199084, 25452441). It is commonly reported in individuals of Norwegian ancestry (PMID: 17574839, 23199084, 25452441). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn1029Argfs*5) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2015

The c.3084_3094delTAATAACATTA pathogenic mutation (also known as3203del11), located in coding exon 9 of the BRCA1 gene, results from a deletion of 11 nucleotides between nucleotide positions 3084 and 3094, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

BRCA1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2024

The BRCA1 c.3084_3094del11 variant is predicted to result in a frameshift and premature protein termination (p.Asn1029Argfs*5). In the literature this variant is also referred to as c.3203del11 or c.3084del11. This variant has been reported in individuals with breast and ovarian cancer (Moller et al. 2001. PubMed: 11334729; Moller et al. 2007. PubMed ID: 17574839; Heramb et al. 2018. PubMed ID: 29339979; Janavicius et al. 2010. PubMed ID: 23199084). Of note, this variant has commonly been reported in individuals of Norwegian descent (Moller et al. 2001. PubMed: 11334729; Janavicius et al. 2010. PubMed ID: 23199084; Heramb et al. 2018. PubMed ID: 29339979). This variant has not been reported in a large population database, indicating this variant is rare, and has been reported as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/54768/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted 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: rs80357647; hg19: chr17-41244453;