rs80357260

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong

The NM_007294.4(BRCA1):c.4183C>T(p.Gln1395*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,456,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q1395Q) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.9993

Clinical Significance

Pathogenic reviewed by expert panel P:29

Conservation

PhyloP100: 6.15

Publications

42 publications found

Variant links:

COSMIC-nc: COSV99066409

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 19 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;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 17-43090946-G-A is Pathogenic according to our data. Variant chr17-43090946-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55125.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.4183C>T	p.Gln1395*	stop_gained, splice_region_variant	Exon 11 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.4183C>T	p.Gln1395*	stop_gained, splice_region_variant	Exon 11 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000412

AC:

AN:

242836

AF XY:

0.00000763

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:

0.00000913

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456324

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723830

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25874

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109274

Other (OTH)

AF:

0.00

AC:

AN:

60182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000501

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:29

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:13

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2021

Baylor Genetics

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

- -

May 28, 2019

Mendelics

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. -

Sep 17, 2012

Sharing Clinical Reports Project (SCRP)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 28, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been reported in individuals and families affected with breast cancer, ovarian cancer and peritoneal carcinoma (Walsh T et al). The variant is reported with the allele frequency of 0.0004118% in gnomAD database and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln1395*) 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 (Borg A et al.). The nucleotide change in BRCA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Mar 07, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PVS1,PM5_STR,PM2_SUP -

Apr 21, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 07, 2022

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous nonsense splice site proximal variation in exon 11 of the BRCA1 gene that results in a stop codon and premature truncation of the protein at codon 1395 was detected . The variant is documented as pathogenic in hereditary breast ovarian cancer syndrome in the ClinVar database. The variant has not been reported in the 1000 genomes and gnomAD databases . The in-silico prediction of the variant is damaging by Mutation Taster2 tool. The reference codon is conserved across species. -

Feb 11, 2015

Institute of Human Genetics, Medical University Innsbruck

Significance:Pathogenic

Review Status:no assertion criteria provided

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

- -

not provided

Pathogenic:6

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BRCA1: PVS1, PM2, PP1, PS4:Supporting -

Jul 22, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant causes the premature termination of BRCA1 protein synthesis. It has been reported in numerous individuals/families with hereditary breast/ovarian cancer syndrome in the published literature (PMID: 31528241 (2019), 31090900 (2019), 30322717 (2018), 29907814 (2018), 29470806 (2018), 29446198 (2018), 29161300 (2017), 27553291 (2016), 27425403 (2016), 26681312 (2015), 26014432 (2015), 24728189 (2014), 24504028 (2014), 23772696 (2014), 22006311 (2011), 16998791 (2006), 16847550 (2006), 11802209 (2002), 8531967 (1996)). -

Jul 29, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 10, 2020

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; 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 4302C>T; This variant is associated with the following publications: (PMID: 31528241, 31090900, 30322717, 29161300, 29446198, 29907814, 30720243, 29470806, 28135048, 26911350, 26681312, 27553291, 27425403, 26986251, 16287141, 25722380, 20104584, 16683254, 24728189, 19941162, 21559243, 25452441, 17949280, 14672397, 27225819, 24504028, 23772696, 16998791, 16847550, 26014432, 8531967, 22006311) -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

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 07, 2021

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.4183C>T (p.Gln1395X) 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 4.1e-06 in 245892 control chromosomes. c.4183C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, one 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. -

Oct 15, 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.Gln1395*) 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 (rs80357260, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer and peritoneal carcinoma (PMID: 8531967, 22006311, 24504028, 26681312, 27553291). This variant is also known as 4302C>T. ClinVar contains an entry for this variant (Variation ID: 55125). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Nov 18, 2024

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 11 of the BRCA1 gene, creating a premature translation stop signal in the BRCA1 protein. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in multiple individuals affected with breast and ovarian cancer (PMID: 8531967, 16760289, 16847550, 22711857, 24728189, 26014432, 26681312, 27553291, 29470806, 30322717, 31090900) and is reported to be a founder mutation in the Tyrolean population in Austria (PMID: 26014432). A multifactorial analysis also has reported a likelihood ratio for pathogenicity based on personal and family history of 2447.175 from log(LR)=3.388664961 for six carriers (PMID: 31853058). This variant has been identified in 1/242836 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. -

Dec 10, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4183C>T (p.Q1395*) alteration, located in exon 11 (coding exon 10) of the BRCA1 gene, consists of a C to T substitution at nucleotide position 4183. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 1395. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of <0.001% (1/242836) total alleles studied. The highest observed frequency was 0.001% (1/109528) of European (non-Finnish) alleles. This mutation has been extensively reported in the literature in individuals with a personal and/or family history of breast and/or ovarian and/or peritoneal cancer and/or colon cancer and associated with somatic loss of heterozygosity (Langston, 1996; Walsh, 2011; Cunningham, 2014; Rashid, 2016; Alemar, 2016; Alemar, 2017; Palmero, 2018; Singh, 2018; Soyano, 2018), as well as in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck, 2018). This alteration has also been shown to be highly prevalent in the Tyrolean population of Austria (Pölsler, 2016). Based on the available evidence, this alteration is classified as pathogenic. -

Familial cancer of breast

Pathogenic:2

Jan 30, 2019

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Sep 25, 2013

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The variant BRCA1:c.4183C>T p.(Gln1395Ter) , which is located in the coding exon 11 of the BRCA1 gene, results from a cytosine-to-thymine substitution at nucleotide position 4183. The glutamine at protein position 1395 is replaced by a premature stop codon which is predicted to cause protein truncation or absence due to non-sense mediated decay. The variant has already been extensively published in unrelated individuals with personal and fammilial history of breast cancer (PMID: 29446198, 22006311, 8531967, 30322717) and also co-segregates with the disease (PMID: 15340362, 20104584, 29907814). It is considered a Tyrolean founder mutation (PMID: 26014432). In the ClinVar database, the variant have multiple entries (25) for Pathogenic or Likely pathogenic (VCV000055125.41) and is assessed as Pathogenic by the ENIGMA expert committee. This variant is very rare in the overall population (no carriers in gnomAD, gnomAD V3.1.2). The variant is classified as Pathogenic. -

Breast and/or ovarian cancer

Pathogenic:1

Aug 09, 2013

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

BRCA1-related cancer predisposition

Pathogenic:1

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4183C>T (p.Gln1395*) variant in the BRCA1 gene is located in exon 11, and is predicted to create a premature termination codon resulting in an absent or disrupted protein product. This variant has been reported in multiple individuals with breast, ovarian and peritoneal carcinoma (PMID: 8531967, 16847550, 16998791, 22006311, 24504028, 24728189, 26014432, 26681312, 27425403, 27553291, 29161300, 29446198, 29470806, 29907814, 30322717, 31090900). This variant has been reported to be a founder mutation in the Tyrolean population (PMID: 26014432). Truncating variants in BRCA1 gene are known to be pathogenic (PMID: 21989022, 17661172, 22762150). This variant is rare (1/242836 chromosomes) in the general population by the Genome Aggregation Database. This variant has been classified as pathogenic by multiple submitters in ClinVar including the expert panel. Therefore the c.4183C>T (p.Gln1395*) variant of the BRCA1 gene is classified as pathogenic. -

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.Gln1395X variant has been previously reported in the literature in 2 of 512 proband chromosomes from individuals with hereditary breast and ovarian cancer and absent from 100 control chromosomes (Langston 1996, Rashid 2006). In addition, this variant is reported in the BIC database 28x as clinically important and the UMD database 35x as causal. This variant leads to a premature stop codon at position 1395, which is predicted to lead to a truncated or absent protein product and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.97

PhyloP100

6.1

Vest4

0.94

GERP RS

4.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

Splicevardb

2.0

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.23

Position offset: -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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over