rs80357662

Positions:

• chr17-43093974-CT-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.1556del​(p.Lys519ArgfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,400 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 ENST00000357654.9 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:23
• Conservation: PhyloP100: 2.46

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 17-43093974-CT-C is Pathogenic according to our data. Variant chr17-43093974-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 17685.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093974-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43093974-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.1556del	p.Lys519ArgfsTer13	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.1556del	p.Lys519ArgfsTer13	frameshift_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461400 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	The c.1556del (p.Lys519Argfs*13) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 8644702, 26718727, 24504028, 18559594, referred as aka 1675delA in some publications]. This variant is a founder mutation in the Swedish population [PMID 8644702]. This one bp deletion in exon 2 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant has not been observed in the ExAC population database. This variant is thus classified as pathogenic -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 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	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM2_supporting; PM5_PTC_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 29, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 09, 2011	- -
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	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Johannsson_1996 Borg_1999 Dorum_1999 Bjorge_2004 Jara_2004 -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2024	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; Common founder variant in the Norwegian population (PMID: 29339979); 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 1675delA; This variant is associated with the following publications: (PMID: 34981296, 37149903, 32923906, 29922827, 28888541, 8644702, 10595257, 23199084, 18559594, 24504028, 26350514, 10441573, 24728189, 26718727, 28637432, 29907814, 30702160, 31447099, 31263571, 10505039, 14522380, 11720839, 32719484, 31825140, 32356124, 30678073, 29371908, 28691938, 26848529, 26681682, 20180971, 37646013, 15515971, 29339979) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 31, 2020	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change creates a premature translational stop signal (p.Lys519Argfs*13) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8644702, 9616287, 11720839, 18559594, 20104584, 24504028, 26718727, 26848529). It is commonly reported in individuals of Norwegian and Swedish ancestry (PMID: 8644702, 9616287, 11720839). This variant is also known as 1675delA. ClinVar contains an entry for this variant (Variation ID: 17685). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 24, 2017	Variant summary: The BRCA1 c.1556delA (p.Lys519Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g., c.1621C>T [p.Gln541X], c.1674delA [p.Gly559fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in the large control database ExAC (0/120854 control chromosomes). The variant has been cited in the literature in breast cancer or ovarian cancer patients numerous times (was identified in at least 20 patients in Judkins_Cancer Res_2005) and is considered a founder mutation in northern Europeans (e.g., see Hoberg-Vetti_BRCA_EJHG_2016 and Soegaard_BRCA1&2_CCR_2008). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2020	The p.Lys519ArgfsX13 variant in BRCA1 has been reported in >100 individuals with BRCA1-related cancer (first reported by Johannson 1996 PMID: 8644702). It was absent from large population studies. This variant was classified as pathogenic on 09/08/16 by the ClinGen-approved ENIGMA expert panel (Variation ID 17685). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 519 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and/or ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2022	The c.1556delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1556, causing a translational frameshift with a predicted alternate stop codon (p.K519Rfs*13). This mutation has been reported in multiple individuals with hereditary breast and ovarian cancer (HBOC) syndrome (Johannsson O et al. Am. J. Hum. Genet. 1996 Mar;58:441-50; Dørum A et al. Eur. J. Cancer. 1997 Dec;33:2390-2; Borg A et al. Dis. Markers. 1999 Oct;15:79-84; Møller P et al. Eur. J. Cancer. 2001 May;37:1027-32; Eccles DM et al. Ann Oncol, 2016 Mar;27:467-73; Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2018 Jan;16:4), including an individual with pancreatic cancer (Bertelsen B et al. NPJ Genom Med, 2019 Jun;4:13). This mutation is a known founder mutation from Norway, and it is one of the four most common BRCA1 mutations identified in individuals of Norwegian ancestry (Janavicius R. EPMA J. 2010 Sep;1:397-412). Of note, this mutation is also designated as 1675delA and K519fs in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 03, 2022	This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1675delA according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in numerous individuals affected with breast cancer and/or ovarian cancer (PMID: 8644702, 15515971, 18559594, 26350514, 26718727, 24504028, 29339979) and is considered a founder mutation in the Norwegian population (PMID 23199084, 29339979). 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

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357662; hg19: chr17-41245991;