rs80357018

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_007294.4(BRCA1):c.3400G>T(p.Glu1134*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,398 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. E1134E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:20

Conservation

PhyloP100: 3.37

Publications

26 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 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-43092131-C-A is Pathogenic according to our data. Variant chr17-43092131-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 37529.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.3400G>T	p.Glu1134*	stop_gained	Exon 10 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.3400G>T	p.Glu1134*	stop_gained	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250824

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:

0.00000753

AC:

AN:

1461398

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111828

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000202

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

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

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1; PM5_PTC_Strong -

Dec 07, 2011

Sharing Clinical Reports Project (SCRP)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 09, 2015

Department of Medical Genetics, Oslo University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

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

- -

Apr 22, 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. -

Jan 14, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:6

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

- -

Nov 16, 2021

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2022

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.3400G>T (p.Glu1134X) 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 allele was found at a frequency of 4e-06 in 250824 control chromosomes. c.3400G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Nedelcu_2002, Thomassen_2008, Pal_2005). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 17, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu1134X variant in BRCA1 has been reported in >20 individuals with BRCA1- associated cancers (Wagner 1999, Bergthorsson 2001, Nedelcu 2002, Pal 2005, Couc h 2015, Rebbeck 2016, Breast Cancer Information Core (BIC) database: https://res earch.nhgri.nih.gov/bic/) and was absent from large population studies. This non sense variant leads to a premature termination codon at position 1134, which is predicted to lead to a truncated or absent protein. Heterozygous loss of functio n of the BRCA1 gene is an established disease mechanism in individuals with here ditary breast and ovarian cancer (HBOC). In addition, this variant was classifie d as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (C linVar SCV000282306.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon presence in m ultiple affected individuals, absence in the general population and predicted im pact to the protein. ACMG/AMP Criteria applied: PVS1; PS4; PM2 (Richards 2015). -

Jan 14, 2025

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.Glu1134*) 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 cancer and ovarian cancer (PMID: 10644434, 11389159, 16284991, 25452441, 26833046, 27376475, 27836010). This variant is also known as 3519G>T. ClinVar contains an entry for this variant (Variation ID: 37529). For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Pathogenic:4

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2021

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. In the published literature, this variant has been reported in affected individuals with breast and/or ovarian cancer (PMIDs: 17688236 (2007), 21233401 (2011), 25452441 (2015), 27376475 (2016), 27836010 (2016), 29339979 (2018), and 29752822 (2018)). Based on the available information, this variant is classified as pathogenic. -

Sep 21, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Bergthorsson 2001, Nedelcu 2002, Pal 2005, Couch 2015, Wei 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3519G>T; This variant is associated with the following publications: (PMID: 10644434, 29446198, 29752822, 31825140, 32380732, 31897316, 25452441, 23704984, 21702907, 16234499, 11748305, 11938448, 21233401, 16284991, 21913181, 19329713, 27221827, 11389159, 27836010, 27376475, 25525159, 29339979, 29805665, 31447099) -

Sep 08, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Feb 26, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E1134* pathogenic mutation (also known as c.3400G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3400. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This alteration has been reported in multiple individuals/families with hereditary breast and/or ovarian cancer (HBOC) (Wagner T et al. Genomics, 1999 Dec;62:369-76; Thomassen M et al. Acta Oncol, 2008;47:772-7; Rebbeck TR et al. Breast Cancer Res, 2016 Nov;18:112; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Wei H et al. Oncol Lett, 2018 Jun;15:9420-9428; Incorvaia L et al. Cancers (Basel), 2020 May;12). Of note, this alteration is also designated as 3519G>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. -

Mar 02, 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 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in at least 10 individuals and families affected with breast and ovarian cancer (PMID: 11389159, 11938448, 16284991, 18465347, 25452441, 27376475, 29339979, 29752822). This variant has been identified in 1/250824 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. -

Inherited breast cancer and ovarian cancer

Pathogenic:1

Apr 09, 2025

NHS Central & South Genomic Laboratory Hub

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.82

PhyloP100

3.4

Vest4

0.84

GERP RS

4.2

PromoterAI

0.0038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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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