rs80357877

Positions:

• chr17-43092039-ACTAGTATCTTC-A

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_3491del​(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:35
• 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/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3481_3491del	p.Glu1161PhefsTer3	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3481_3491del	p.Glu1161PhefsTer3	frameshift_variant	10/23	1	NM_007294.4	P4

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:35

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:14

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 16, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 31, 2018	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. -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Medical University Innsbruck	Feb 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 08, 2023	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. -

not provided Pathogenic:12

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Aug 17, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 28, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BRCA1: PVS1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 02, 2023	PP5, PM2, PS4_moderate, PVS1 -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 02, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 04, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 09, 2021	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. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2023	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

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

Ovarian neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

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;