chr17-43063946-C-A

Position:

• chr17-43063946-C-A

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.5080G>T​(p.Glu1694*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:18 O:1
• Conservation: PhyloP100: 3.32

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 17-43063946-C-A is Pathogenic according to our data. Variant chr17-43063946-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 55387.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063946-C-A is described in Lovd as [Pathogenic]. Variant chr17-43063946-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5080G>T	p.Glu1694*	stop_gained	17/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5080G>T	p.Glu1694*	stop_gained	17/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251136 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461734 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727172

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

Alfa AF: 0.000106 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 07, 2023	- -
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)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 05, 2006	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 29, 2022	This nonsense variant causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/251136 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMIDs: 28111427 (2017), 29020732 (2018), 29446198 (2018), 30207098 (2018), 31825140 (2019), 32019277 (2020), 32455662 (2020), and 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1)). The variant is found to impact splicing by skipping exon 18 and creating an in-frame deletion within the highly conserved BRCT1 domain (PMIDs: 9497265 (1998) and 18391021 (2008)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2020	Nonsense variant in the C-terminus predicted to result in the in-frame skipping of exon 17, also denoted exon 18, resulting in disruption of the BRCT domain (Mazoyer 1998, Liu 2001, Perrin-Vidoz 2002); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Shattuck-Eidens 1997, Liu 2001, Schoumacher 2001, Meindl 2002, Kim 2012); Published functional studies demonstrate a damaging effect: classified as non-functional based a saturation genome editing assay measuring cell viability (Findlay 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 9497265, 11137998, 12393792, 27281844, 31924417, 32098980, 30207098, 32019277, 29673794, 25863477, 27026398, 29446198, 28111427, 30209399, 29020732, 25525159, 18391021, 12145750, 22798144, 16825284, 16267036, 12955719, 11802209, 11400546, 9333265, 29346284) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 19, 2022	- -

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	Dec 01, 2023	This sequence change creates a premature translational stop signal (p.Glu1694*) in the BRCA1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs80356896, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9333265, 9497265). This variant is also known as 5199G>T. ClinVar contains an entry for this variant (Variation ID: 55387). Studies have shown that this premature translational stop signal results in skipping of exon 17, but is expected to preserve the integrity of the reading-frame (PMID: 11137998). This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Asp1692_Phe1717del) have been determined to be pathogenic (PMID: 9497265). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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	Oct 28, 2024	Variant summary: BRCA1 c.5080G>T (p.Glu1694X) 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. Publications report experimental evidence that this variant affects mRNA splicing and results in the in-frame skipping of exon 18 (also referred to as exon 17 in the literature; e.g. Mazoyer_1998, Liu_2001), an exon in which multiple variants have been classified as pathogenic by our laboratory and others in ClinVar, supporting the critical relevance of this region to BRCA1 function. The variant allele was found at a frequency of 4e-06 in 251136 control chromosomes. c.5080G>T has been reported in the literature in multiple individuals/families affected with Hereditary Breast And Ovarian Cancer Syndrome (eg. Mazoyer_1998, Loader_1998a, Loader_1998b, Judkins_2005, Kim_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11137998, 16267036, 10464609, 22798144, 9333265, 10464601, 25863477, 9497265). ClinVar contains an entry for this variant (Variation ID: 55387). 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	Color Diagnostics, LLC DBA Color Health	Apr 12, 2021	This variant changes 1 nucleotide in exon 17 of the BRCA1 gene, creating a premature translation stop signal. This sequence change is expected to result in an absent or non-functional protein product. In addition, RNA studies have shown that this variant disrupts an exonic splice enhancer motif and causes aberrant splicing, resulting in an in-frame skipping of exon 17 (exon 18 based on BIC nomenclature; p.Asp1692_Phe1717del) (PMID: 9497265, 11137998). The mutant protein lacking 26 amino acids from the conserved BRCT domain is expected to be dysfunctional. This variant has been reported in over ten individuals affected with breast cancer (PMID: 9497265, 10464631, 11802209, 22798144, 25863477). This variant has been identified in 1/251136 chromosomes 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 03, 2023	The c.5080G>T (p.E1694*) alteration, located in exon 17 (coding exon 16) of the BRCA1 gene, consists of a G to T substitution at nucleotide position 5080. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 1694. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This pathogenic mutation has been reported in numerous individuals with personal and/or family histories consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Shattuck-Eidens, 1997; Kang, 2015; Eoh, 2017; Park 2017; Kwon, 2019; Kim, 2018; Rebbeck, 2018). This pathogenic mutation has also been reported in a double heterozygote state in conjunction with a BRCA2 mutation (Loader, 1998). Functional analyses have shown this pathogenic mutation results in disruption of an ESE motif leading to skipping of coding exon 17 of the BRCA1 gene and that it has a deleterious impact on cell survival in a high throughput genome editing assay (Ambry internal data; Mazoyer, 1998; Liu, 2001; Goina, 2008; Findlay, 2018). Of note, this alteration is also designated as 5199G>T in published literature. Based on the available evidence, this alteration is classified as pathogenic. -

BRCA1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2024

The BRCA1 c.5080G>T variant is predicted to result in premature protein termination (p.Glu1694*). This variant has been reported in multiple individuals with breast and/or ovarian cancer (Shattuck-Eidens et al. 1997. PubMed ID: 9333265; Park et al. 2017. PubMed ID: 28111427; Table S2, Eoh et al. 2017. PubMed ID: 29020732; reported as c.5199G>T in Mazoyer et al. 1998. PubMed ID: 9497265). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and it is classified as pathogenic by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/55387/). Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.89
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.40		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs80356896; hg19: chr17-41215963;