rs80357919

Variant names:

• chr17-43094684-ATGAG-A
• rs80357919
• NM_007294.4:c.843_846delCTCA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.843_846delCTCA​(p.Ser282TyrfsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S281S) has been classified as Likely benign. 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 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:36
• Conservation: PhyloP100: 4.22
• Publications: 31 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 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 17-43094684-ATGAG-A is Pathogenic according to our data. Variant chr17-43094684-ATGAG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17683.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	c.843_846delCTCA	p.Ser282TyrfsTer15	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.843_846delCTCA	p.Ser282TyrfsTer15	frameshift_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461474 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726994

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111724

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:36

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:15

May 24, 2021

Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Jul 13, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 28, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2015

Department of Medical Genetics, Oslo University Hospital

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. -

Dec 09, 2022

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1, PS4_STR, PM2_SUP -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

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

- -

May 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 04, 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 -

May 28, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

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

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM2_supporting; PM5_PTC_Strong -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:11

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 4 nucleotide from exon 11 of the BRCA1 mRNA (c.843_846delCTCA), causing a frameshift after codon 282 and the creation of a premature translation stop signal 15 amino acid residues later- p.(Ser282Tyrfs). This is expected to result in an absent or disrupted protein product.Truncating variants in BRCA1 are known to be pathogenic. This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747).This mutation has been described in the mutation database ClinVar (Variation ID: 17683). -

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

- -

Aug 23, 2024

Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital

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.Ser282TyrfsX15 variant has been reported in 25 of 3463 probands with breast or ovarian cancer (Anton-Culver_2000_10882857, Capalbo_2006_16760289, Wagner_1998_9663595, Zhang_2011_21324516, Machackova_2008_18489799, Janezic_1999_10196379, http://research.nhgri.nih.gov/bic/). In addition, The p.Ser282TyrfsX15 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 282 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants are an established mechanism of disease for the BRCA1 gene, which makes it highly likely that the p.Ser282TyrfsX15 variant is pathogenic. -

Jan 05, 2021

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; Reported in numerous individuals with personal and/or family histories of breast and/or ovarian cancer (Wagner 1998, Janezic 1999, Stegel 2011, Zhang 2011, Pern 2012, Song 2014, Muendlein 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 962del4 and 962_965delCTCA; This variant is associated with the following publications: (PMID: 10196379, 9663595, 21324516, 23110154, 22366370, 21232165, 23397983, 23635950, 24797986, 24728189, 27221827, 25971625, 27533253, 26306726, 25066507, 18489799, 11179017, 27062684, 29339979, 28324225, 31159747, 32341426, 26681312) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

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 25, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.843_846del (p.Ser282Tyrfs*15) 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 affected with breast and/or ovarian cancer (PMIDs: 29785153 (2018), 23110154 (2012), 21324516 (2011)). 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. -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Dec 30, 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.Ser282Tyrfs*15) 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 breast and/or ovarian cancer (PMID: 9663595, 10196379, 17319787, 21203900, 21324156, 23110154). This variant is also known as 962del4. ClinVar contains an entry for this variant (Variation ID: 17683). 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

- -

Jun 19, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser282TyrfsX15 variant in BRCA1 has been reported in 23 individuals with BRCA1-related cancers (first published by Wagner 1998 PMID: 9663595). It was absent from large population studies. This variant was classified as pathogenic on 09/08/16 by the ClinGen-approved ENIGMA expert panel (Variation ID 17683). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 282 and leads to a premature termination codon 15 amino acids downstream. This alteration is then 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/or ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PM2. -

Apr 30, 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.843_846delCTCA (p.Ser282TyrfsX15) 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 254112 control chromosomes (gnomAD and publication data). c.843_846delCTCA has been reported in the literature in multiple individuals affected with breast cancer and/or ovarian cancer (Wagner_1998, Janezic_1999, Judkins_2005, Song_2014, 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. Twelve ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Breast and/or ovarian cancer Pathogenic:2

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2000

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 20, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.843_846delCTCA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of four nucleotides at positions 843 to 846, causing a translational frameshift with a predicted alternate stop codon (p.S282Yfs*15). This mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer (Janezic SA et al. Hum. Mol. Genet. 1999;8:889-97; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Wagner TM et al. Int. J. Cancer. 1998 July;77:354-60; Tihomirova L et al. Adv Med Sci. 2014 Mar;59:114-9; Pern F et al. PLoS ONE. 2012 Oct;7:e47993; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Dobricic J et al. J. Hum. Genet. 2013 Aug;58:501-7; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). Of note, this mutation is also designated as 962del4 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. -

May 31, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 962del4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 5 individuals affected with ovarian cancer and two dozen individuals affected with breast cancer (PMID: 9808526, 10196379, 21324516, 23110154, 24728189, 24797986, 26681312, 29785153, 30441849). 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;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Jul 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:1

Mar 13, 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80357919; hg19: chr17-41246701;