17-43094514-CTT-CTTT

Variant names:

• chr17-43094514-C-CT
• rs80357569
• NM_007294.4:c.1016dupA

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.1016dupA​(p.Val340GlyfsTer6) 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 1,461,720 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: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:32
• Conservation: PhyloP100: 0.0760

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 17-43094514-C-CT is Pathogenic according to our data. Variant chr17-43094514-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 54102.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.1016dupA	p.Val340GlyfsTer6	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.1016dupA	p.Val340GlyfsTer6	frameshift_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461720 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:32

Revision: reviewed by expert panel

Submissions by phenotype

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

Jun 25, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 23, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

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. -

Jul 01, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1016dupA (p.Val340Glyfs*6) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple families with hereditary breast and ovarian cancer (PMID 7894492, 10441573, 18489799, 28184945) and two individuals with sporadic breast cancer (PMID 23289006). This variant has not been observed in general population databases. Therefore, the c.1016dupA (p.Val340Glyfs*6) variant in the BRCA1 gene is classified as pathogenic. -

Dec 06, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PVS1, PM2,SUP, PS4 -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:10

Dec 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.1016dup; p.Val340GlyfsTer6 variant (rs80357569), also known as 1135insA in traditional nomenclature, is reported in the literature in several individuals affected with hereditary breast and/or ovarian cancer, and is considered a founder variant in the Norwegian and Swedish populations (selected publications Dorum 1999, Foretova 2004, Janavicius 2010, Laraqui 2013, Machackova 2008). This variant is also reported in ClinVar (Variation ID: 54102), absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Dorum A et al. Penetrances of BRCA1 1675delA and 1135insA with respect to breast cancer and ovarian cancer. Am J Hum Genet. 1999 Sep;65(3):671-9. PMID: 10441573. Foretova L et al. BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic. Hum Mutat. 2004 Apr;23(4):397-8. PMID: 15024741. Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. EPMA J. 2010 Sep;1(3):397-412. PMID: 23199084. Laraqui A et al. Mutation screening of the BRCA1 gene in early onset and familial breast/ovarian cancer in Moroccan population. Int J Med Sci. 2013;10(1):60-7. PMID: 23289006. Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008 May 20;8:140. PMID: 18489799. -

Feb 22, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM2, PS4_moderate, PVS1 -

Apr 23, 2021

AiLife Diagnostics, AiLife Diagnostics

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

Classification criteria: ENIGMA 5 -

May 27, 2022

Human Genetics Bochum, Ruhr University Bochum

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used to clasify this variant: PVS1, PM2, PS4 -

Nov 23, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a pathogenic founder variant in the Norwegian population (Dorum 1999, Rudkin 2006, Torres-Mejia 2014); 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 individuals and families with Hereditary Breast and Ovarian Cancer (Borg 1999, Foretova 2004, Laraqui 2013, Yablonski-Peretz 2016); Not observed at a significant frequency 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 1135dupA, 1135insA, and 1128insA; This variant is associated with the following publications: (PMID: 10595257, 15024741, 25371446, 26687385, 16287141, 23199084, 23034506, 32231684, 26350514, 10441573, 23289006, 16509964, 25814778, 18489799, 23697973, 25884701, 26845104, 28993866, 28724667, 27062684, 7894492, 28184945, 26295337, 28637432, 29673794, 28776284, 29339979, 30702160, 30078507, 30322717, 28111427, 31411802) -

Apr 04, 2021

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 individuals with breast/ovarian cancer in the published literature (PMID: 28724667 (2017), 26350514 (2015), 25186627 (2015), 23289006 (2013), 18489799 (2008), 7894492 (1994)). Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:6

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

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2020

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.1016dupA (p.Val340GlyfsX6) 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 251174 control chromosomes (gnomAD). c.1016dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Simard_1994, Ramus_2007, Palma_2008, Spearman_2008, Laraqui_2013). These data indicate that the variant is very likely to be associated with disease. Ten ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 01, 2015

Curoverse

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Frameshifts in BRCA1 are considered pathogenic, and this is a BRCA1 Val340Gly frameshift variant in exon 10 -

Dec 22, 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.Val340Glyfs*6) 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: 10441573, 15024741, 18489799, 23199084, 23289006). This variant is also known as 1135insA. ClinVar contains an entry for this variant (Variation ID: 54102). For these reasons, this variant has been 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

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Apr 06, 2021

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 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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over 10 individuals and families affected with breast and ovarian cancer (PMID: 7894492, 8755943, 10441573, 15024741, 17688236, 18703817, 23289006, 26350514, 27062684, 28724667) and found to segregate with disease in several members of one family (PMID: 17688236). This variant also has been described as a founder mutation in Sweden and Norway (PMID: 8755943, 10441573, 23199084). 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 01, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1016dupA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of A at nucleotide position 1016, causing a translational frameshift with a predicted alternate stop codon (p.V340Gfs*6). This mutation has been detected in multiple breast and/or ovarian cancer families (Foretova L et al. Hum. Mutat., 2004 Apr;23:397-8; Machackova E et al. BMC Cancer, 2008 May;8:140; Laraqui A et al. Int J Med Sci, 2013 Dec;10:60-7; Høberg-Vetti H et al. Eur J Hum Genet, 2016 06;24:881-8; Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Meynard G et al. Oncol. Rep., 2017 Mar;37:1573-1578; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Concolino P et al. Int J Mol Sci, 2019 Jul;20; Bu H et al. J Obstet Gynaecol Res, 2019 Nov;45:2267-2274; El Ansari FZ et al. BMC Cancer, 2020 Aug;20:747). This mutation has been described as a founder mutation originating from the Eastern population of Norway and Sweden (Dørum A et al. Am. J. Hum. Genet. 1999 Sep;65:671-9; Janaviius R. EPMA J. 2010 Sep;1:397-412; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3). Of note, this alteration is also designated as 1135insA and 1128insA 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. -

Breast and/or ovarian cancer Pathogenic:1

Apr 14, 2010

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

BRCA1-related cancer predisposition Pathogenic:1

Aug 31, 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 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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over 10 individuals and families affected with breast and ovarian cancer (PMID: 7894492, 8755943, 10441573, 15024741, 17688236, 18703817, 23289006, 26350514, 27062684, 28724667) and found to segregate with disease in several members of one family (PMID: 17688236). This variant also has been described as a founder mutation in Sweden and Norway (PMID: 8755943, 10441573, 23199084). 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. -

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

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: rs80357569; hg19: chr17-41246531;