Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5035del(p.Leu1679Ter) 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 1,461,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L1679L) has been classified as Likely benign. 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
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PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
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PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43067646-AG-A is Pathogenic according to our data. Variant chr17-43067646-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 55358.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067646-AG-A is described in Lovd as [Pathogenic]. Variant chr17-43067646-AG-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
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Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Feb 20, 2004
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Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Sep 08, 2016
Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Nov 17, 2010
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Pathogenic, no assertion criteria provided
clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center
May 05, 2023
A known pathogenic mutation was detected in the BRCA1 gene (c.5098delC) This sequence change creates a premature translational stop signal (p.Leu1700*) 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 ovarian cancer (PMID: 21156238, 22752604, 22874498, 26911350). This variant is also known as 5154delC, and c.5035del. ClinVar contains an entry for this variant (Variation ID: 55358) with 12 submissions. Therefore, this variant has been classified as Pathogenic. This variant was confirmed by Sanger sequencing. -
Pathogenic, criteria provided, single submitter
clinical testing
Molecular Endocrinology Laboratory, Christian Medical College
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Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Apr 23, 2016
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not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter
clinical testing
Revvity Omics, Revvity
Sep 24, 2021
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Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Jul 11, 2014
This deletion of one nucleotide is denoted BRCA1 c.5035delC at the cDNA level and p.Leu1679Ter (L1679X) at the protein level. The normal sequence, with the base that is deleted in brackets, is TTAT[C]TAAT. The deletion causes a frameshift resulting in a nonsense variant, which changes a Leucine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.5035delC, also published as BRCA1 c.5154delC using alternate nomenclature, has been observed in cases of familial breast cancer (Juwle 2012, Manguoglu 2010). -
Uncertain significance, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
The c.5035delC pathogenic mutation, located in coding exon 15 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 5035, causing a translational frameshift with a predicted alternate stop codon (p.L1679*). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 May;39:593-620). Specifically, this variant has been reported in Indian and Pakistani patients with breast and/or ovarian cancer and is a proposed founder mutation (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Rashid MU et al. Hered Cancer Clin Pract, 2019 Sep;17:27; Sunar V et al. Asia Pac J Clin Oncol, 2022 Feb;18:84-92; Rashid MU et al. Int J Cancer, 2022 Aug;151:402-411). Of note, this variant is also designated as 5154del 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. -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Sep 25, 2023
This variant deletes 1 nucleotide in exon 16 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 individuals and families affected with breast and ovarian cancer (PMID: 21156238, 22752604, 22874498, 26911350, 27553291, 31528241, 33629534, 35377489). 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. -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
GeneKor MSA
Jul 01, 2016
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Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Jan 16, 2024
This sequence change creates a premature translational stop signal (p.Leu1679*) 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 ovarian cancer (PMID: 21156238, 22752604, 22874498, 26911350). This variant is also known as 5154delC. ClinVar contains an entry for this variant (Variation ID: 55358). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -