rs80357877

Variant names:

• chr17-43092039-ACTAGTATCTTC-A
• rs80357877
• NM_007294.4:c.3481_3491delGAAGATACTAG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.3481_3491delGAAGATACTAG​(p.Glu1161PhefsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:37
• Conservation: PhyloP100: 3.40

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 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 17-43092039-ACTAGTATCTTC-A is Pathogenic according to our data. Variant chr17-43092039-ACTAGTATCTTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 17684.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092039-ACTAGTATCTTC-A is described in Lovd as [Pathogenic]. Variant chr17-43092039-ACTAGTATCTTC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3481_3491delGAAGATACTAG	p.Glu1161PhefsTer3	frameshift_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.3481_3491delGAAGATACTAG	p.Glu1161PhefsTer3	frameshift_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461770 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:37

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:13

Mar 02, 2020

BRCAlab, Lund University

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

- -

Sep 16, 2014

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Feb 11, 2015

Institute of Human Genetics, Medical University Innsbruck

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 31, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.3481_3491del (p.Glu1161Phefs*3) variant in exon 10 of the BRCA1 gene causes a frame shift that creates an early stop codon which is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been reported in patients and families with hereditary breast cancer and ovarian cancer (PMID: 7611277, 10196379, 15131401, 22006311, 23199084, 25880076) and is not observed in general population databases. Therefore, the c.3481_3491del (p.Glu1161Phefs*3) variant in the BRCA1 gene is classified as pathogenic. -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 15, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 23, 2021

MGZ Medical Genetics Center

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. -

May 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 24, 2014

Pathway Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:13

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1: PVS1, PM2, PS4:Moderate -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 07, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM2, PS4_moderate, PVS1 -

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

- -

Oct 28, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift 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 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 3600del11; This variant is associated with the following publications: (PMID: 21120943, 12955716, 25880076, 22006311, 10196379, 7611277, 20104584, 16528604, 27756336, 28263838, 26295337, 23479189, 22010008, 10946349, 16457150, 9760198, 12827452, 25862976, 25722380, 26329992, 26287763, 26720728, 28008555, 21305653, 15131401, 29550896, 28493033, 9150149, 21702907, 16267036, 27062684, 28125078, 26681312, 23199084, 30322717, 30736435, 31447099) -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 17, 2018

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.3481_3491del (p.Glu1161Phefs*3) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals/families with breast and/or ovarian cancer (PMID: 35264596 (2022), 29550896 (2019), 30322717 (2018), 28493033 (2018), 26720728 (2016), 10196379 (1999), 7611277 (1995)), fallopian tube carcinoma (PMID: 22006311 (2011)), pancreatic cancer (PMID: 30736435 (2019)), and Ewing sarcoma (PMID: 28125078 (2017)). In addition, this variant is described as a French founder variant (PMID: 29550896 (2019), 28493033 (2018), 23199084 (2010)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Aug 04, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu1161fs variant in BRCA1 has been reported as a founder variant in the F rench population (Muller 2004, Janavicius 2010) that has been observed in more t han >70 individuals with BRCA1-associated cancers (Struewing 1995, Janezic 1999, Muller 2004, Breast Cancer Information Core (BIC) database). It was also absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 1161 and l eads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism for hereditary b reast and ovarian cancer (HBOC). Additionally, the p.Glu1161fs variant was class ified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert pane l (ClinVar SCV000282308.1). In summary, this variant meets our criteria to be cl assified as pathogenic for autosomal dominant HBOC. -

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

- -

Jan 02, 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.3481_3491del11 (p.Glu1161PhefsX3) 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 was absent in 251276 control chromosomes. c.3481_3491del11 has been widely 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) 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 21, 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.Glu1161Phefs*3) 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 a personal and family history of breast and ovarian cancer (PMID: 7611277, 10196379, 12955716, 15131401, 23199084). It is commonly reported in individuals of French ancestry (PMID: 7611277, 10196379, 12955716, 15131401, 23199084). This variant is also known as 3600del11 and 3600_3610del11. ClinVar contains an entry for this variant (Variation ID: 17684). For these reasons, this variant has been classified as Pathogenic. -

Jul 02, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Nov 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3481_3491del11 pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 11 nucleotides at nucleotide positions 3481 to 3491, causing a translational frameshift with a predicted alternate stop codon (p.E1161Ffs*3). This mutation has been identified in multiple individuals with hereditary breast and/or ovarian cancer (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Struewing JP et al. Am. J. Hum. Genet. 1995 Jul;57:1-7; Janezic SA et al. Hum. Mol. Genet. 1999 May;8:889-97; Díez O et al. Hum. Mutat. 2003 Oct;22:301-12; Azzollini J et al Eur. J. Intern. Med. 2016 Jul;32:65-71). This mutation was reported to account for approximately 37% of BRCA1 mutations in France, indicating a possible founder effect (Janaviius R. EPMA J. 2010 Sep;1:397-412). Of note, this alteration is also designated as 3600del11 in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 11 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3600del11 and c.3481_3491del11 in the literature. 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 multiple families and individuals affected with breast and ovarian cancer (PMID: 7611277, 9150149, 9760198, 10196379, 12955716, 15131401, 22006311, 23199084, 25880076, 26287763, 26681312, 27062684), in a breast cancer case-control meta-analysis in 6/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000258), and has been suggested to be a common founder mutation in France (PMID: 15131401). This variant has not been identified 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

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

BRCA1-related cancer predisposition Pathogenic:1

Aug 19, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 11 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3600del11 and c.3481_3491del11 in the literature. 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 multiple families and individuals affected with breast and ovarian cancer (PMID: 7611277, 9150149, 9760198, 10196379, 12955716, 15131401, 22006311, 23199084, 25880076, 26287763, 26681312, 27062684), in a breast cancer case-control meta-analysis in 6/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000258), and has been suggested to be a common founder mutation in France (PMID: 15131401). This variant has not been identified 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. -

Familial cancer of breast Pathogenic:1

Oct 01, 2024

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 -

Ovarian neoplasm Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357877; hg19: chr17-41244056;