17-43093856-CTT-CT

Position:

• chr17-43093856-CTT-CT

Variant summary

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

The NM_007294.4(BRCA1):​c.1674delA​(p.Gly559fs) 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:20
• Conservation: PhyloP100: 0.540

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]

BRCA1 (HGNC:):

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 17-43093856-CT-C is Pathogenic according to our data. Variant chr17-43093856-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 37425.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093856-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43093856-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.1674delA	p.Gly559fs	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.1674delA	p.Gly559fs	frameshift_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7

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	Sharing Clinical Reports Project (SCRP)	Jul 16, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 03, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	case-control	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	May 24, 2021	- -
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. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 03, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 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; Reported in association with hereditary breast and ovarian cancer (Geisler et al., 2002; Dworkin et al., 2009; Rodriguez et al., 2012; Blay et al., 2013; de Juan Jimenez et al., 2013); 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 1793delA; This variant is associated with the following publications: (PMID: 31921681, 11304778, 11773283, 31825140, 34413315, 23683081, 23479189, 9145677, 19340607, 22044689, 16267036, 28024868, 29659587, 28528518, 29752822) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 11, 2021	This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been identified in individuals with breast cancer and ovarian cancer in the published literature (PMID: 31921681 (2019), 29446198 (2018), 28680148 (2017), 22044689 (2012), 11773283 (2002), 9145677 (1997)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 23, 2024	PM2, PM5_strong, PVS1 -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Gly559Valfs*13 variant was identified in 5 of 5020 proband chromosomes (frequency: 0.001) from individuals or families with non-hereditary diffuse gastric cancer, breast or ovarian cancer and was not identified in 2340 chromosomes from population-matched controls (Blay 2013, Couch 1997, de Juan Jimenez 2013, Sahasrabudhe 2017, Torres 2017). The variant was also identified in dbSNP (ID: rs80357600) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx, and nine other submitters), COGR (1x pathogenic), LOVD 3.0 (6x pathogenic), BIC Database (6x with clinical importance), and in ARUP Laboratories database (definitely pathogenic). The variant was not identified in Cosmic, UMD-LSDB, or Zhejiang University databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.1674del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 559 and leads to a premature stop codon at position 571. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer (HBOC) syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

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 05, 2024	This sequence change creates a premature translational stop signal (p.Gly559Valfs*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: 9145677, 11773283, 23479189, 23683081). This variant is also known as 1790delA and 1793delA. ClinVar contains an entry for this variant (Variation ID: 37425). 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	Aug 09, 2019	Variant summary: BRCA1 c.1674delA (p.Gly559ValfsX13) 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 250426 control chromosomes (gnomAD). c.1674delA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018). 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. Eight ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 02, 2024	The c.1674delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1674, causing a translational frameshift with a predicted alternate stop codon (p.G559Vfs*13). This mutation has been reported in patients with personal and/or family histories suspicious for Hereditary Breast and Ovarian Cancer (Couch FJ et al. N. Engl. J. Med. 1997 May;336:1409-15; Geisler JP et al. J Natl Cancer Inst, 2002 Jan;94:61-7; Shih HA et al. J Clin Oncol, 2002 Feb;20:994-9; Dworkin AM et al. Fam Cancer, 2009 Apr;8:339-46; Rodríguez AO et al. Gynecol Oncol, 2012 Feb;124:236-43; Blay P et al. BMC Cancer. 2013 May;13:243; de Juan Jiménez I et al. Fam Cancer, 2013 Dec;12:767-77; Briceño-Balcázar I et al. Colomb Med (Cali), 2017 Jun;48:58-63; Torres D et al. Sci Rep, 2017 07;7:4713 Cock-Rada AM et al. Fam Cancer, 2018 01;17:23-30; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Wei H et al. Oncol Lett, 2018 Jun;15:9420-9428; Li JY et al. Int J Cancer, 2019 01;144:281-289; Oliver J et al. Front Oncol, 2019 Dec;9:1429). Of note, this alteration has also been reported as 1790delA and 1793delA 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 16, 2020	This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 11773283, 23479189, 23683081, 28680148, 28528518). 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. -

Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili

Nov 07, 2023

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

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: rs80357600; hg19: chr17-41245873;