chr17-43124030-C-CT

Variant names:

• chr17-43124030-C-CT
• rs80357783
• NM_007294.4:c.66dupA

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.66dupA​(p.Glu23ArgfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:40 U:1
• Conservation: PhyloP100: -0.118

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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1696 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43124030-C-CT is Pathogenic according to our data. Variant chr17-43124030-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 37691.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.66dupA	p.Glu23ArgfsTer18	frameshift_variant	Exon 2 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.66dupA	p.Glu23ArgfsTer18	frameshift_variant	Exon 2 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460784 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726790

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:40 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:12 Uncertain:1

Feb 15, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 11, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35918668 (2022), 35220195 (2022), 34290354 (2021), 32733560 (2020), 29470806 (2018), 29176636 (2018)) and endometrial cancer (PMID: 31492746 (2019)). 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. -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change inserts one nucleotide in exon 2 of BRCA1 mRNA (c.66dupA), causing a frameshift at codon 23 and the creation of a premature translation stop signal 18 amino acid residues later. This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This variant is also known as 185insA in the literature and it has been reported in the literature in individuals and families with breast and/or ovarian cancer (PMID: 8595420, 20189727, 24916970, 16998791). The mutation database ClinVar contains entries for this variant (Variation ID: 37691). -

Mar 31, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with personal or family history consistent with pathogenic variants in this gene (PMID: 16287141, 16998791, 20189727, 18627636, 24916970, 29339979, 20950396); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 185dup; This variant is associated with the following publications: (PMID: 8595420, 27157322, 10952777, 29339979, 29752822, 16287141, 30078507, 29053726, 34981296, 36367610, 34601666, 36243179, 35918668, 38167124, 31492746, 20189727, 26187060, 22798144, 25103822, 23374397, 24916970, 20950396, 18627636, 12181777, 28179634, 27257965, 16998791, 29907814, 29116469, 29433453, 28993434, 8807330, 30702160, 27553291, 29470806, 28176296, 31528241, 32733560, 32341426, 29176636, 31742824, 31825140, 30787465, 11597388, 35220195, 34290354, 32211327, 15026808, 35264596, 35377489, 31892343, 33461583, 38219492, 37851290) -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2014

Eurofins Ntd Llc (ga)

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

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

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

Jul 26, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

Jul 01, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 08, 2023

Baylor Genetics

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. -

Mar 02, 2020

BRCAlab, Lund University

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

- -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 20, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu23Argfs*18) 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: 8595420, 12181777, 16998791, 20189727, 24916970). This variant is also known as 185insA. ClinVar contains an entry for this variant (Variation ID: 37691) classified as pathogenic , reviewed by expert panel. For these reasons, this variant has been classified as Pathogenic. -

-

Molecular Endocrinology Laboratory, Christian Medical College

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

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 29, 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.Glu23Argfs*18) 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: 8595420, 12181777, 16998791, 20189727, 24916970). This variant is also known as 185insA. ClinVar contains an entry for this variant (Variation ID: 37691). 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

- -

Jun 14, 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.66dupA (p.Glu23Asnfs) 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. p.Gln60X, p.Tyr101X, p.Glu143X, etc.). This variant is absent in 120930 control chromosomes from ExAC. The variant is a recurrent pathogenic variant found in several HBOC patients/families and in individuals undergoing BRCA1/2 testing. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -

Nov 16, 2021

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:3

Nov 16, 2018

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 30, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Center for Precision Medicine, Meizhou People's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Dec 20, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 10, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 2 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 reported in at least 10 Individuals affected with breast and ovarian cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected individual (PMID: 8595420, 11606101, 12181777, 18627636, 20189727, 20950396, 27257965, 28993434, 29152070, 29470806, 33471991, 35918668; Leiden Open Variation Database DB-ID BRCA1_001098), and in suspected hereditary breast and ovarian cancer families (PMID: 10952777, 16683254, 16998791, 21559243, 24916970, 25863477, 29176636, 29339979, 29907814). This variant also has been reported in an individual affected with melanoma (PMID: 29433453). 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. -

Aug 30, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.66dupA pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a duplication of one nucleotide at position 66, causing a translational frameshift with a predicted alternate stop codon (p.E23Rfs*18). This mutation has been described in numerous breast and ovarian cancer patients and families (Couch FJ and Weber BL. Hum. Mutat. 1996;8:8-18; Rashid MU et al. Int. J. Cancer. 2006 Dec;119:2832&ndash;39; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Bujassoum SM et al. J. Cancer Sci. Ther. 2017;9(2):358-64). Of note, this alteration is also designated as 185insA 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. -

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

Apr 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA1-related cancer predisposition Pathogenic:1

Sep 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 2 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 Individuals affected with breast and ovarian cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected individual (PMID: 8595420, 11606101, 12181777, 18627636, 20189727, 20950396, 27257965, 28993434, 29152070, 29470806, 33471991, 35918668; Leiden Open Variation Database DB-ID BRCA1_001098), and in suspected hereditary breast and ovarian cancer families (PMID: 10952777, 16683254, 16998791, 21559243, 24916970, 25863477, 29176636, 29339979, 29907814). This variant also has been reported in an individual affected with melanoma (PMID: 29433453). 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 neoplasm Pathogenic:1

Nov 01, 2015

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

BRCA1-related disorder Pathogenic:1

Aug 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 c.66dupA variant is predicted to result in a frameshift and premature protein termination (p.Glu23Argfs*18). This variant is alternatively referred to as 185insA. This variant has been reported in many individuals and families with breast and/or ovarian cancer (Matsushima et al. 1995. PubMed ID: 8595420; Couch et al. 1996. PubMed ID: 8807330; Liede et al. 2002. PubMed ID: 12181777; Rashid et al. 2006. PubMed ID: 16998791; Noël et al. 2010. PubMed ID: 20189727; PubMed ID: 24916970; Arai et al. 2017. PubMed ID: 29176636; Heramb et al. 2018. PubMed ID: 29339979; Li et al. 2018. PubMed ID: 29752822; Bhaskaran et al. 2019. PubMed ID: 30702160). It has also been reported in a male individual with melanoma (Ibrahim et al. 2018. PubMed ID: 29433453). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37691/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

- -

Breast carcinoma Pathogenic:1

Aug 08, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357783; hg19: chr17-41276047;