rs80357123

Variant names:

• chr17-43057078-G-A
• rs80357123
• NM_007294.4:c.5251C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43057078-G-A
• chr17-43057078-G-C
• chr17-43057078-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5251C>T​(p.Arg1751*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,918 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: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:43 O:2
• Conservation: PhyloP100: 2.15

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-43057078-G-A is Pathogenic according to our data. Variant chr17-43057078-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55480.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43057078-G-A is described in Lovd as [Pathogenic]. Variant chr17-43057078-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5251C>T	p.Arg1751*	stop_gained	Exon 19 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5251C>T	p.Arg1751*	stop_gained	Exon 19 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152116 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251492 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135920

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: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727206

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: 0.0000187

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152116 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74302

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:43 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:19 Other:2

Feb 11, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breast Cancer Information Core (BIC) (BRCA1)

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Mar 02, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Dec 14, 2020

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

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 29, 2023

Human Genetics Bochum, Ruhr University Bochum

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used to clasify this variant:PVS1, PS4_MOD, PM2_SUP -

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

- -

Sep 16, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 25, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5251C>T (p.Arg1751*) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 9361038, 21324516, referred as c.5370C>T] and prostate cancer [PMID 27433846]. This variant creates a premature stop codon at amino acid position 1751 of the BRCA1 protein. This variant is thus predicted to result in a loss of function of the protein. This variant has not been observed in the ExAC population database. This variant thus classified as pathogenic. -

May 16, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS3,PS4,PM2_SUP -

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

- -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Molecular Endocrinology Laboratory, Christian Medical College

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2015

Institute of Human Genetics, Medical University Innsbruck

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:11

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Arg1751X variant has been previously reported in the literature in at least 14 of 6217 individuals with hereditary breast and ovarian cancer and was consistent with a pathogenic role for this variant (Vehmanen 1997, Zhang 2011, Ladopoulou 2002, Schulz 2012, Papi 2009, Risch 2006, Krajc 2008, Sarantaus 2001, Fostira 2012). In a limited number of control chromosomes (186) the variant was not identified in these studies. This variant was also listed in the UMD (13x), LOVD, COSMIC and BIC (33x as clinically important) databases. The p.Arg1751X variant results in a premature stop codon at position 1751, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants in 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. -

Oct 11, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.5251C>T (p.Arg1751*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 34529195 (2021), 32341426 (2020), 31825140 (2019), 29752822 (2018), 29339979 (2018), 28324225 (2017)), prostate cancer (PMID: 27433846 (2016)), ovarian cancer (PMID: 21324516 (2011)), and leukemia (PMID: 35534704 (2022)). The frequency of this variant in the general population, 0.000014 (4/282892 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 28, 2022

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 (Vehmanen 1997, Sarantaus 2001, Stavropoulou 2013, Churpek 2015, Szwiec 2015, Alemar 2016, Pritchard 2016, Brovkina 2018); Published functional studies demonstrate a damaging effect: unable to support viability in a haploid cell line (Findlay 2018); Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5370C>T; This variant is associated with the following publications: (PMID: 24528374, 26852015, 27393621, 27514839, 18783588, 17148771, 23199084, 29310832, 21324516, 25525159, 9361038, 26287763, 23536787, 26843898, 26779294, 27167707, 27082205, 27425403, 27756336, 27533253, 27836010, 27433846, 20614009, 24010542, 21232165, 18821011, 16528604, 28324225, 28985766, 23469205, 29339979, 29752822, 29907814, 28993434, 28724667, 22652532, 22434525, 12142080, 11436123, 18159056, 25428789, 17453335, 30209399, 30333958, 31174498, 30702160, 29161300, 30078507, 29446198, 28176296, 30199306, 32295079, 33084842, 30787465, 34011307, 31447099, 32341426, 31825140) -

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

- -

Dec 08, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM2, PS3_supporting, PVS1 -

Sep 30, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Oct 18, 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: The BRCA1 c.5251C>T (p.Arg1751X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. c.5266dupC (p.Glh1756fsX74), c.5289delG (p.Leu1764X), and c.5335delC (p.Gln1779fsX14)). The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple databases/clinical diagnostic laboratories cite the variant as "Pathogenic/Causal." Therefore, the variant of interest has been classified as Pathogenic. -

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1751X variant in BRCA1 has been identified in >50 individuals with BRCA1-associated cancers (Konstantopoulou 2014 PMID: 17453335, Stegal 2011 PMID:21232165, Stavropoulou 2013 PMID: 23536787, Breast Cancer Information Core (BIC) database). It has also been identified in 0.005% (1/19954) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA Expert Panel (Variation ID 55480). This nonsense variant leads to a premature termination codon at position 1751, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PM2. -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a single base substitution, replacing Arginine with a termination codon. It is expected to result in a truncated, non-functional protein. Truncating variants in BRCA1 are known to be pathogenic. This particular variant is also known as 5370C>T and it has been described in the literature in multiple individuals with breast and ovarian cancer (PMID 21324516, 9361038) and in an individual with prostate cancer (PMID: 27433846). The mutation database ClinVar contains entries for this variant (Variation ID: 55480). -

Sep 08, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS4 moderated, PM2 moderated -

Jan 22, 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.Arg1751*) 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 (rs80357123, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with prostate cancer and breast and ovarian cancer (PMID: 9361038, 21232165, 21324516, 24010542, 25428789, 27433846). This variant is also known as 5370C>T. ClinVar contains an entry for this variant (Variation ID: 55480). 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

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Sep 26, 2022

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 19 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been reported in over 20 individuals affected with breast and ovarian cancer (PMID: 12142080, 17453335, 18159056, 21324516, 23469205, 23536787, 24010542, 25428789, 26287763, 27393621, 30287823, 32856862, 33471991, 35205313; Leiden Open Variation Database DB-ID BRCA1_000435) and an individual affected with prostate cancer (PMID: 27433846). This variant has been identified in 94 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 4/282892 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. -

Nov 30, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1751* pathogenic mutation (also known as c.5251C>T), located in coding exon 18 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5251. This changes the amino acid from an arginine to a stop codon within coding exon 18. This mutation has been reported in multiple breast and/or ovarian cancer families from various ethnicities to date and has been described as a European founder mutation (Vehmanen P et al. Hum. Mol. Genet. 1997 Dec;6:2309-15; Sinilnikova OM et al. Fam. Cancer. 2006;5:15-20; Papi L et al. Breast Cancer Res. Treat. 2009 Oct;117:497-504; Janaviius R. EPMA J. 2010 Sep;1:397-412; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Konstantopoulou I et al. Clin. Genet. 2014 Jan;85:36-42; Szwiec M et al. Clin. Genet. 2015 Mar;87:288-92; Zhang J et al. Breast Cancer Res. Treat. 2016 Aug;158:455-62; Alemar B et al. Cancer Genet. 2016 Sep;209:417-422; Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18:112; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). This mutation has also been reported in gastric cancer patients (awniczak M et al. Hered Cancer Clin Pract. 2016 Jan;14:3), as well as in a study of men with metastatic prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Of note, this mutation is also designated as 5370C>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. -

Feb 05, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Breast and/or ovarian cancer Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast neoplasm Pathogenic:1

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Familial cancer of breast Pathogenic:1

Oct 17, 2018

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.77	D
Vest4		0.88
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs80357123; hg19: chr17-41209095; COSMIC: COSV58785164;