rs80357989

Variant names:

• chr17-43094680-T-TGTAATGA
• rs80357989
• NM_007294.4:c.844_850dupTCATTAC

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.844_850dupTCATTAC​(p.Gln284LeufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 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: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:16 U:1
• Conservation: PhyloP100: 1.50

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 17-43094680-T-TGTAATGA is Pathogenic according to our data. Variant chr17-43094680-T-TGTAATGA is described in ClinVar as [Pathogenic]. Clinvar id is 55735.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.844_850dupTCATTAC	p.Gln284LeufsTer5	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.844_850dupTCATTAC	p.Gln284LeufsTer5	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: 1461682 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727108

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 1998

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

- -

Oct 18, 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 -

Hereditary breast ovarian cancer syndrome Pathogenic:4

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

- -

Aug 04, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gln284fs variant in BRCA1 has been reported in >10 Caucasian individuals with BRCA1-associated cancers (Ozcelik 2003, Stegel 2011, Krajc 2014) and was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 284 and leads to a premature stop codon 5 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 breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for autosomal dominant HBOC. -

Jan 15, 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.Gln284Leufs*5) 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 pancreatic ductal adenocarcinoma and a personal and/or family history of breast and/or ovarian cancer (PMID: 12920083, 16287141, 22923021, 23635950, 25940717, 26306726, 28740454). ClinVar contains an entry for this variant (Variation ID: 55735). For these reasons, this variant has been classified as Pathogenic. -

Aug 12, 2024

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.844_850dupTCATTAC (p.Gln284LeufsX5) 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. The variant was absent in 251110 control chromosomes. c.844_850dupTCATTAC has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Stegel_2011, Ozcelik_2003, Krajc_2014, van der Stoep_2009). 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. The following publications have been ascertained in the context of this evaluation (PMID: 21232165, 12920083, 23397983, 19370767). ClinVar contains an entry for this variant (Variation ID: 55735). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3 Uncertain:1

Nov 02, 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 individuals with breast, ovarian, and pancreatic cancers in the published literature (PMID: 30940100 (2019), 26306726 (2015), 25940717 (2015), 23635950 (2013), 12920083 (2003)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic. -

Mar 31, 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 963_969dupTCATTAC, 963-969 dup, and 969ins7; This variant is associated with the following publications: (PMID: 28740454, 32772980, 35220195, 21232165, 19370767, 24312913, 22923021, 26852130, 23635950, 23397983, 25940717, 26306726, 30940100, 12920083) -

Jul 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.844_850dup; p.Gln284LeufsTer5 variant (rs80357989, ClinVar Variation ID: 55735), also known as 969ins7, is a recurrent variant found frequently in the Slovenian population, and is reported in the literature in several individuals and families affected with breast and/or ovarian cancer (Bora 2022, Dobricic 2013, Krajc 2014, Minucci 2015, Nguyen-Dumont 2020, Novakovic 2012, Ozcelik 2003, Stegel 2011), and pancreatic adenocarcinoma (Holter 2015). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by duplicating seven nucleotides, 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: Bora E et al. Evaluation of hereditary/familial breast cancer patients with multigene targeted next generation sequencing panel and MLPA analysis in Turkey. Cancer Genet. 2022 Apr;262-263:118-133. PMID: 35220195. Dobricic J et al. Serbian high-risk families: extensive results on BRCA mutation spectra and frequency. J Hum Genet. 2013 Aug;58(8):501-7. PMID: 23635950. Holter S et al. Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma. J Clin Oncol. 2015 Oct 1;33(28):3124-9. PMID: 25940717. Krajc M et al. Geographical distribution of Slovenian BRCA1/2 families according to family origin: implications for genetic screening. Clin Genet. 2014 Jan;85(1):59-63. PMID: 23397983. Minucci A et al. Clinical impact on ovarian cancer patients of massive parallel sequencing for BRCA mutation detection: the experience at Gemelli hospital and a literature review. Expert Rev Mol Diagn. 2015;15(10):1383-403. PMID: 26306726. Nguyen-Dumont T et al. Genetic testing in Poland and Ukraine: should comprehensive germline testing of BRCA1 and BRCA2 be recommended for women with breast and ovarian cancer? Genet Res (Camb). 2020 Aug 10;102:e6. PMID: 32772980. Novakovic S et al. Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families. Int J Oncol. 2012 Nov;41(5):1619-27. PMID: 22923021. Ozcelik H et al. Individual and family characteristics associated with protein truncating BRCA1 and BRCA2 mutations in an Ontario population based series from the Cooperative Family Registry for Breast Cancer Studies. J Med Genet. 2003 Aug;40(8):e91. PMID: 12920083. Stegel V et al. The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population. BMC Med Genet. 2011 Jan 14;12:9. PMID: 21232165. -

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jun 30, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 7 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 969ins7 and 970ins7 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 detected in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 12920083, 23635950, 26852130) including recurrent affected families in Slovenia (PMID: 22923021). 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. -

Jul 17, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.844_850dupTCATTAC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of TCATTAC at nucleotide position 844, causing a translational frameshift with a predicted alternate stop codon (p.Q284Lfs*5). This mutation has been reported in several high-risk breast/ovarian cancer families (Ozcelik H, J. Med. Genet. 2003 Aug; 40(8):e91; Stegel V et al. BMC Med Genet, 2011 Jan;12:9; Novakovi S et al. Int J Oncol, 2012 Nov;41:1619-27; Dobrii J et al. J Hum Genet, 2013 Aug;58:501-7; Krajc M et al. Clin Genet, 2014 Jan;85:59-63; Minucci A et al. Expert Rev Mol Diagn, 2015 Aug;15:1383-403; Cini G et al. BMC Med Genet, 2016 Feb;17:11; Cvelbar M et al. Radiol Oncol, 2017 Jun;51:187-194; Gornjec A et al. BMC Cancer, 2019 Apr;19:296; Nguyen-Dumont T et al. Genet Res (Camb), 2020 08;102:e6) as well as in a pancreatic cancer cohort (Holter S et al. J Clin Oncol, 2015 Oct;33:3124-9). In particular, this mutation has been reported frequently in the Slovenian population (Stegel V et al. BMC Med Genet, 2011 Jan;12:9; Novakovi S et al. Int J Oncol, 2012 Nov;41:1619-27; Krajc M et al. Clin Genet, 2014 Jan;85:59-63). Of note, this alteration is also referred to as 969ins7, 970ins7, and 850_851insTCATTAC in the 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. -

BRCA1-related cancer predisposition Pathogenic:1

Sep 28, 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 7 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 969ins7 and 970ins7 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 detected in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 12920083, 23635950, 26852130) including recurrent affected families in Slovenia (PMID: 22923021). 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. -

Rhabdomyosarcoma Pathogenic:1

Aug 10, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs80357989; hg19: chr17-41246697;