Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2767_2770delGTTA(p.Val923IlefsTer76) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,164 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 17-43092760-TTAAC-T is Pathogenic according to our data. Variant chr17-43092760-TTAAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 54678.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092760-TTAAC-T is described in Lovd as [Pathogenic]. Variant chr17-43092760-TTAAC-T is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4
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 14, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Jun 20, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Dec 23, 2015
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:2
Feb 10, 2025
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.2767_2770delGTTA (p.Val923IlefsX76) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4e-06 in 251024 control chromosomes (gnomAD). c.2767_2770delGTTA has been reported in the literature in individuals affected with tumors that belong to the Hereditary Breast and Ovarian Cancer (HBOC) syndrome tumor spectrum (e.g. Pritchard 2016, Susswein 2015, and in the BIC database). The following publications have been ascertained in the context of this evaluation (PMID: 26681312, 27433846). ClinVar contains an entry for this variant (Variation ID: 54678). Based on the evidence outlined above, the variant was classified as pathogenic. -
Mar 18, 2023
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.Val923Ilefs*76) 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 (rs80357661, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with prostate cancer or endometrial cancer (PMID: 26681312, 27433846). ClinVar contains an entry for this variant (Variation ID: 54678). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
May 09, 2014
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This deletion of 4 nucleotides is denoted BRCA1 c.2767_2770delGTTA at the cDNA level and p.Val923IlefsX76 (V923IfsX76) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GACA[GTTA]ATAT. The deletion causes a frameshift, which changes a Valine to an Isoleucine at codon 923, and creates a premature stop codon at position 76 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider This variant, also known as c.2886_2889delGTTA using alternate nomenclature, to be pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.2767_2770delGTTA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 2767 to 2770, causing a translational frameshift with a predicted alternate stop codon (p.V923Ifs*76). This alteration was identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med., 2016 Aug;375:443-53) and in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). 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. -