Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2216_2217delAA(p.Lys739SerfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 17-43093313-CTT-C is Pathogenic according to our data. Variant chr17-43093313-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 54504.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093313-CTT-C is described in Lovd as [Pathogenic]. Variant chr17-43093313-CTT-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4
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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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. -
Mar 30, 2009
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Dec 03, 2017
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Pathogenic:2
Jun 23, 2021
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 (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2335_2336delAA; Observed in individuals with BRCA1-related cancers (Yassaee 2002, Azzollini 2016, Shi 2017); This variant is associated with the following publications: (PMID: 12100744, 12442265, 27062684, 27165220, 26187060, 27535533, 30702160, 28176296, 31825140) -
Jan 29, 2018
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.2216_2217delAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 2216 to 2217, causing a translational frameshift with a predicted alternate stop codon (p.K739Sfs*3). This mutation has been reported in several unrelated individuals from diverse populations with early onset breast or ovarian cancer (Yassaee VR et al. Breast Cancer Res., 2002 Apr;4(4):R6; Azzollini J et al. Eur J Intern Med 2016 Jul;32:65-71; Shi T et al. Int J Cancer 2017 05;140(9):2051-2059). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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. -
Jan 15, 2020
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 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Jun 12, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys739Serfs*3) 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 premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12100744, 27062684, 28176296). This variant is also known as c.2335_2336delAA. ClinVar contains an entry for this variant (Variation ID: 54504). For these reasons, this variant has been classified as Pathogenic. -
Familial cancer of breast Other:1
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Genomic Research Center, Shahid Beheshti University of Medical Sciences