rs80357310

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_007294.4(BRCA1):c.3661G>T(p.Glu1221*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,864 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: 6.8e-7 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:19

Conservation

PhyloP100: 4.92

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 17-43091870-C-A is Pathogenic according to our data. Variant chr17-43091870-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 54957.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091870-C-A is described in Lovd as [Pathogenic]. Variant chr17-43091870-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.3661G>T	p.Glu1221*	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.3661G>T	p.Glu1221*	stop_gained	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251298

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:5

Mar 24, 2022

Baylor Genetics

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. -

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

- -

Jan 17, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 30, 1999

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 13, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This pathogenic variant is denoted BRCA1 c.3661G>T at the cDNA level and p.Glu1221Ter (E1221X) at the protein level. The substitution creates a nonsense variant, changing a Glutamic Acid to a premature stop codon (GAA>TAA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also reported as 3780G>T using alternate nomenclature, has been reported in association with hereditary breast and ovarian cancer (Peelen 1997, Dong 1998, Claes 2004, De Leeneer 2012, Hasmad 2015) and is considered pathogenic. -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1: PVS1, PM2 -

Mar 05, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Jul 11, 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.Glu1221*) 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 present in population databases (rs80357310, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150151, 21553119, 25452441, 26541979). This variant is also known as 3780G>T. ClinVar contains an entry for this variant (Variation ID: 54957). 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

- -

Mar 28, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: This c.3661G>T variant results in a premature termination codon in exon 10, predicted to cause a truncated or absent BRCA1 protein. Heterozygous loss-of-function due to mutations in this gene is an established disease mechanism in HBOC or HBOC-related cancers. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Glu1373X, p.Gln1395X, p.Tyr1853X, etc.). This variant was found in 1/121338 control chromosomes from the large and broad populations of ExAC at a frequency of 0.0000082, which does not exceed the maximal expected frequency of a pathogenic allele (0.0010005) in this gene. This variant has been reported in several patients with HBOC in literature and clinical databases. Multiple clinical labs as well as reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant or Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Jan 10, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1221* pathogenic mutation (also known as c.3661G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3661. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This alteration has been identified in multiple cohorts of individuals diagnosed with breast, ovarian and pancreatic cancer and has been recognized as a founder mutation in the Belgian population (Peelen T et al. Am. J. Hum. Genet. 1997 May;60:1041-9; Claes K et al. Br. J. Cancer. 2004 Mar;90:1244-51; Janaviius R. EPMA J. 2010 Sep;1:397-412; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Hasmad HN et al. Gynecol. Oncol., 2016 05;141:318-322; Shindo K et al. J. Clin. Oncol., 2017 Oct;35:3382-3390; Blair AB et al. J. Am. Coll. Surg., 2018 04;226:630-637.e1; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Li A et al. Gynecol. Oncol., 2018 10;151:145-152). This alteration has also been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15) and was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Of note, this mutation is also designated as 3780G>T in the 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. -

Nov 16, 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. This variant has been reported in at least 10 individuals affected with breast, ovarian or pancreatic cancer (PMID: 11733976, 11802209, 15026808, 25452441, 26541979, 30078507, 30093976, 33471991; Leiden Open Variation Database DB-ID BRCA1_001444) and in two dozen families suspected to be affected with hereditary breast and ovarian cancer (PMID: 9150151, 9760198, 29446198). This variant also has been described as a recurrent mutation in individuals affected with breast and ovarian cancer from Belgium (PMID: 15026808). This variant has been identified in 1/251298 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. -

Breast and/or ovarian cancer

Pathogenic:1

Aug 26, 2013

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast neoplasm

Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Malignant tumor of breast

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Glu1221X variant has been previously reported in the literature in at least 8 of 4008 chromosomes from individuals with hereditary breast and ovarian cancer (Baeyens 2004, Claes 2004, Judkins 2005, Meindl 2002 , Peelen 1997). It has also been observed in public databases including BIC (9x as clinically important) and in the UMD (1x). The variant was also reported in dbSNP and in the exome variant server 1 in 8599 eurapean alleles and may be a low frequency pathogenic variant (rs80357310). The p.Glu1221X variant leads to a premature stop codon at position 1221, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are a known mechanism of mutation in hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. -

BRCA1-related disorder

Pathogenic:1

Mar 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 c.3661G>T variant is predicted to result in premature protein termination (p.Glu1221*). This variant has been reported in individuals with breast cancer and ovarian cancer or pancreatic cancer (examples, Table 1. Claes et al 2004. PubMed ID: 15026808; Supplementary Table 2. Couch et al 2014. PubMed ID: 25452441; eTable 1. Blair et al 2018. PubMed ID: 29309945). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic in ClinVar including expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/54957/). In summary, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.97

Vest4

0.85

GERP RS

5.3

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over