Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2649_2650insGGCA(p.Thr884GlyfsTer20) 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 17-43092881-T-TTGCC is Pathogenic according to our data. Variant chr17-43092881-T-TTGCC is described in ClinVar as [Pathogenic]. Clinvar id is 254417.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3
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. -
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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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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Hereditary breast ovarian cancer syndrome Pathogenic:2
Apr 08, 2020
Center of Medical Genetics and Primary Health Care
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
ACMG Guidelines 2015 criteria The BRCA1 p.Thr884Glyfs is a known pathogenic variant in exon 11 in a non-functional domain just before the BRSTCANCERI domain (S1180-1200Q aa) (PMID: 10198641) and in a mutational hotspot with 37 pathogenic variants (PM1 Pathogenic Moderate). This frameshift variant truncates the protein and potentially hinder HRR as an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). The variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299802.2) (PP5 Pathogenic Supporting). In this study this variant was found in a 36-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic. -
Jan 22, 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.Thr884Glyfs*20) 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 cancer (PMID: 25186627, 27165220, 33558524). ClinVar contains an entry for this variant (Variation ID: 254417). For these reasons, this variant has been classified as Pathogenic. -
Familial breast and ovarian cancer Pathogenic:1
Mar 01, 2020
Center of Medical Genetics and Primary Health Care
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
ACMG Guidelines 2015 criteria The BRCA1 p.Thr884Glyfs is a known pathogenic variant in exon 11 in a non-functional domain just before the BRSTCANCERI domain (S1180-1200Q aa) (PMID: 10198641) and in a mutational hotspot with 37 pathogenic variants (PM1 Pathogenic Moderate). This frameshift variant truncates the protein and potentially hinder HRR as an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). The variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299802.2) (PP5 Pathogenic Supporting). In this study this variant was found in a 36-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.2649_2650insGGCA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from an insertion of 4 nucleotides at position 2649, causing a translational frameshift with a predicted alternate stop codon (p.T884Gfs*20). This alteration has been seen in multiple breast cancer cohorts (Tung N et al. Cancer, 2015 Jan;121:25-33; Yassaee VR et al. Asian Pac. J. Cancer Prev., 2016;17:149-53). 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. -