Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1360_1361delAG(p.Ser454fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,764 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.
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]
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 17-43094169-ACT-A is Pathogenic according to our data. Variant chr17-43094169-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 37406.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094169-ACT-A is described in Lovd as [Pathogenic]. Variant chr17-43094169-ACT-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:10
Aug 26, 2022
BRCAlab, Lund University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Jan 01, 2015
Department of Medical Genetics, Oslo University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Oct 12, 2018
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.1360_1361delAG (p.Ser454*) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with hereditary breast and ovarian cancer (PMID 10528853, 11056688, 17148771), and has been reported 19 times in Breast Cancer Information Core. This variant is observed at a low minor allele frequency (2/245828) in gnomAD. Therefore, the c.1360_1361delAG (p.Ser454*) variant in the BRCA1 gene is classified as pathogenic. -
May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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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. -
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
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
The BRCA1 p.Ser454X variant was identified in at least 5 of 112950 proband chromosomes (frequency: 0.00004) from individuals or families with hereditary breast or ovarian cancer (Judkins 2005, Ottini 2000, Risch 2001, van Orsouw 1999). The variant was also previously identified by our laboratory in 1 individual with breast and ovarian cancer. The variant was identified in dbSNP (ID: rs80357969) “With Pathogenic allele”, and the BIC database (19X as Pathogenic). The p.Ser454X variant leads to a premature stop codon at position 454, which is predicted to lead to 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. -
May 01, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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May 24, 2021
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: case-control
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Oct 22, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Pathogenic:6
Mar 25, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individual and families with breast and ovarian cancer in the published literature (PMID: 31209999 (2019), 26219728 (2016), 11056688 (2000)). Based on the available information, this variant is classified as pathogenic. -
Nov 10, 2020
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Nonsense 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 association with breast and ovarian cancer (Ottini 2000, Zhang 2011); 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 know as c.1479_1480delAG; 1479delAG; This variant is associated with the following publications: (PMID: 31447099, 10528853, 21324516, 11179017, 28087643, 11056688, 22874498, 26681312, 17148771, 27062684, 29339979, 30720243) -
Nov 25, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Feb 08, 2024
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Dec 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
BRCA1: PVS1, PM2, PS4:Moderate -
Jun 03, 2014
Clinical Genetics and Genomics, Karolinska University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:4
Jan 19, 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.Ser454*) 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 present in population databases (rs80357969, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10528853, 22874498, 26219728, 26681312). This variant is also known as 1479delAG. ClinVar contains an entry for this variant (Variation ID: 37406). For these reasons, this variant has been classified as Pathogenic. -
Dec 09, 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.1360_1361delAG (p.Ser454Terfs) 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. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121340 (1/60670), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest was reported in multiple affected individuals via publications. In addition, multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest 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
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Jul 02, 2018
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.1360_1361delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 1360 to 1361, causing a translational frameshift with a predicted alternate stop codon (p.S454*). This alteration has been reported in several unrelated individuals diagnosed with breast and/or ovarian cancer (van Orsouw NJ et al. J. Med. Genet. 1999 Oct;36(10):747-53; Ottini L et al. Breast Cancer Res. 2000 Mar;2(4):307-10; Risch HA et al. J. Natl. Cancer Inst. 2006 Dec 6;98(23):1694-706; Ozcelik H et al. J. Mol. Diagn. 2012 Sep;14(5):467-75; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71; Plaskocinska I et al. J. Med. Genet. 2016 Oct;53(10):655-61; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3). Of note, this alteration is also designated as 1479delAG 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. -
Nov 07, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant deletes 2 nucleotides 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 is also known as 1479delAG based on Breast Cancer Information Core (BIC) nomenclature. This variant has been reported in over twenty individuals affected with breast and/or ovarian cancer, and in high-risk breast and ovarian cancer families (PMID: 10528853, 11056688, 11938448, 17148771, 21324516, 22874498, 26219728, 26681312, 27208206, 32245699, 32438681, 33403015, 33471991). This variant has been identified in 29 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 2/251004 chromosomes 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 and/or ovarian cancer Pathogenic:1
Jun 12, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Pathogenic
Review Status: criteria provided, single submitter