chr17-43063946-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_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 (★★★). Synonymous variant affecting the same amino acid position (i.e. E1694E) has been classified as Uncertain significance. 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

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:18

Conservation

PhyloP100: 3.32

Publications

36 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia, complementation group S
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pancreatic cancer, susceptibility to, 4
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.5080G>T	p.Glu1694*	stop_gained	Exon 17 of 23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.5080G>T	p.Glu1694*	stop_gained	Exon 17 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251136

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461734

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111906

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000506

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:7

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 05, 2006

Sharing Clinical Reports Project (SCRP)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

Variant allele predicted to encode a truncated non-functional protein. -

Feb 07, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:5

Jul 29, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 19, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Apr 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Oct 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 12, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 29, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E1694* pathogenic mutation (also known as c.5080G>T), located in coding exon 16 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5080. This changes the amino acid from a glutamic acid to a stop codon within coding exon 16. 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 D et al. JAMA, 1997 Oct;278:1242-50; Kang E et al. Breast Cancer Res. Treat., 2015 May;151:157-68; Eoh KJ et al. Cancer Res Treat, 2017 Sep; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Kwon BS et al. Cancer Res Treat 2019 Oct. Kim DH et al. J Gynecol Oncol, 2018 Nov;29(6):e90; Rebbeck TR et al. Hum. Mutat., 2018 05;39(5):593-620). This pathogenic mutation has also been reported in a double heterozygote state, in conjunction with a BRCA2 mutation (Loader S et al. Genet. Test., 1998;2:75-7). 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 S et al. Am. J. Hum. Genet., 1998 Mar;62:713-5; Liu HX et al. Nat. Genet., 2001 Jan;27:55-8; Goina E et al. Mol. Cell. Biol., 2008 Jun;28:3850-60; Findlay GM et al. Nature. 2018 10;562(7726):217-222). Of note, this alteration is also designated as 5199G>T 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. -

BRCA1-related disorder

Pathogenic:1

Jul 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.90

PhyloP100

3.3

Vest4

0.89

GERP RS

5.8

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

3.0

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

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chr17-43063946-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over