17-43093459-CTT-CT

Variant names:

• chr17-43093459-CT-C
• rs80357688
• NM_007294.4:c.2071delA

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.2071delA​(p.Arg691AspfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,742 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: 0.0000034 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:28
• Conservation: PhyloP100: 0.831
• Publications: 28 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 17-43093459-CT-C is Pathogenic according to our data. Variant chr17-43093459-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 37444.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.2071delA	p.Arg691AspfsTer10	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.2071delA	p.Arg691AspfsTer10	frameshift_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461742 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727166

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:11

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, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 07, 2017

Bioinformatics dept., Datar Cancer Genetics Limited, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 13, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2015

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

May 25, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.2071del variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) BRCA1:c.2071del is a deletion of a single nucleotide in exon 11 predicted to encode a frame-shift in translation of the mature mRNA with consequent premature termination of protein synthesis at codon 10 of the frame-shift, or 701 (BRCA1 p.(Arg691AspfsTer10):) using NP_009225.1. This is expected to result in disrupted or absent protein product due to nonsense mediated decay (NMD). If NMD is escaped, this variant is expected to encode a truncated protein. Variants of this type are widely accepted to be pathogenic (Tayoun et al., 2018 PMID:30192042). BRCA1:c.2071del (rs80357688) is absent in population databases (gnomAD) and is not on record in FLOSSIES. BRCA1:c.2071del (also described as BRCA1 2190delA using legacy nomenclature) has been reported in multiple unrelated individuals with breast and/or ovarian cancer (Zhang et al., 2011 PMID: 21324516, Cunningham et al., 2014 PMID: 24504028, Ow et al., 2019 PMID: 30875412, George et al., 2021 PMID: 33646313). BRCA1:c.2071del is on record in ClinVar (Variation ID: CD982486) reported by multiple clinical laboratories as pathogenic in association with Hereditary breast and ovarian cancer. This variant is listed in HGMD as ‘disease causing mutation’ in association with Breast cancer (Accession: CD982486). -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 06, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in at least 10 individuals affected with breast, ovarian, and fallopian tube cancer (PMID: 9482581, 9667259, 10359546, 11179017, 12354934, 17369502, 21324516, 23458327, 24240112, 24504028, 24728189, 25371446, 26287763, 30875412, 33646313) and an individual affected with prostate cancer (PMID: 23569316). 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. -

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

- -

Jun 02, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:7

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 15, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 16, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 2025

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 at 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 2190delA; This variant is associated with the following publications: (PMID: 21324516, 10486320, 24728189, 23942203, 19471317, 9482581, 17148771, 23569316, 26287763, 24504028, 25371446, 25452441, 23458327, 25556971, 11437066, 17369502, 27534398, 28127413, 30875412, 24950059, 34347777, 31897316, 35186721, 27533253, 24830819, 26295337, 33758026, 33646313, 38170500, 36169650) -

Dec 14, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in symptomatic individuals with breast and/or ovarian cancer in the published literature (PMIDs: 9482581 (1998), 21324516 (2011), 24504028 (2014), and 26287763 (2015)). Based on the available information, this variant is classified as pathogenic. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Arg691AspfsX10 deletion variant was identified in 7 of 9116 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian, or prostate cancer (Castro 2013, Gayther 1999, Jongsma 2002, Risch 2001, Kurian 2008, Zhang 2011). The variant was also identified in dbSNP (ID: rs80357688) “With pathogenic allele”, HGMD, UMD (1X as a causal variant), and the BIC database (24X with clinical importance). The p.Arg691AspfsX10 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 691 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2017

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.2071delA (p.Arg691Aspfs) 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.2138C>G, p.Ser713X; c.2157dupA, p.Glu720fs). One in silico tool predicts a damaging outcome for this variant. The variant of interest is absent in a large, broad control population, ExAC in 121338 control chromosomes. This variant was reported in multiple patients with HBOC (Judkins_2005, Trujillano_2014, Peto_1999, Frank_1998, Risch_2001, Zhang_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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

- -

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with a risk of breast and ovarian cancer (MIM#604370), fanconi anemia, complementation group S (MIM#617883) and other types of cancer (OMIM). (I). 0108 - This gene is associated with both recessive and dominant disease. Autosomal recessive inheritance of variants is associated with fanconi anaemia, complementation group S (MIM#617883), whilst autosomal dominant inheritance is associated with an increased risk for familial breast and/or ovarian cancer, 1 (MIM#604370), or pancreatic cancer susceptibility, 4 (MIM#614320). The gene has also been reported to be associated with increased risk for prostate and stomach cancer (PMID: 26236408). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, Gene Reviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2.1.1 and v3). (SP) 0701 - Other variants comparable to the one identified in this case has very strong previous evidence for pathogenicity. Multiple frameshift and nonsense variants throughout the gene have been reported to be pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. ClinVar: Pathogenic x18 including a submission by an Expert Review panel. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign -

Oct 21, 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.Arg691Aspfs*10) 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 family history of breast and/or ovarian cancer (PMID: 9482581, 9667259, 10486320, 21324516, 24504028). This variant is also known as 2190delA. ClinVar contains an entry for this variant (Variation ID: 37444). For these reasons, this variant has been classified as Pathogenic. -

Breast and/or ovarian cancer Pathogenic:2

Mar 31, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2009

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

Apr 11, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2071delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2071, causing a translational frameshift with a predicted alternate stop codon (p.R691Dfs*10). This mutation has been observed in multiple breast and/or ovarian cancer families (Andersen TI et al. Hum. Mutat. 1998;11:166-74; Frank TS et al. J Clin Oncol, 1998 Jul;16:2417-25; Peto J et al. J. Natl. Cancer Inst. 1999 Jun;91:943-9; Jongsma AP et al. Mol Pathol, 2002 Oct;55:305-9; Judkins T et al. Cancer Res, 2005 Nov;65:10096-103; Konecny M et al. Breast Cancer Res Treat. 2011 Feb;126:119-30; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Akbari MR et al. Clin. Genet. 2014 Jan;85:64-7; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Torres-Mejía G et al. Cancer Epidemiol. Biomarkers Prev. 2015 Mar;24:498-505; Pal T et al. Cancer. 2015 Dec;121:4173-80) and in a prostate cancer patient (Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57). Of note, this alteration is also designated as 2190delA and 2187delA in the 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. -

Feb 24, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in at least 10 individuals affected with breast, ovarian, and fallopian tube cancer (PMID: 9482581, 9667259, 10359546, 11179017, 12354934, 17369502, 21324516, 23458327, 24240112, 24504028, 24728189, 25371446, 26287763, 30875412, 33646313) and an individual affected with prostate cancer (PMID: 23569316). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 250.326 from log(LR)=2.398505926 for 7 carriers (PMID: 31853058).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. -

Fanconi anemia, complementation group S Pathogenic:1

Feb 28, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 9482581, 24504028, 21324516] -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.83
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: rs80357688; hg19: chr17-41245476;