Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2766delA(p.Val923LeufsTer77) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 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 17-43092764-CT-C is Pathogenic according to our data. Variant chr17-43092764-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 54677.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092764-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43092764-CT-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:9
May 01, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Jul 29, 2021
Baylor Genetics
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.Val923LeufsX77 variant was identified in 1 of 86 proband chromosomes (frequency: 0.012) from Singaporean individuals or families with early onset breast cancer and was not identified in 100 control chromosomes from healthy individuals (Ho 2000). The variant was also identified in dbSNP (ID: rs80357812) “With Pathogenic allele”, HGMD, the BIC database (1X with pathogenic clinical importance), and UMD (1X as a causal variant). The variant was identified in the ClinVar database with multiple submissions: Sharing Clinical Reports Project (SCRP) (derived from Myriad reports) as pathogenic, BIC as pathogenic, and INVITAE with classification not provided. The p.Val923LeufsX77 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 923 and leads to a premature stop codon 77 codons downstream. This alteration is then predicted to result in 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. -
Nov 03, 2014
Michigan Medical Genetics Laboratories, University of Michigan
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
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. -
Jun 22, 1999
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
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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Sep 21, 2015
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant deletes 1 nucleotide 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. -
Dec 23, 2021
Sema4, Sema4
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation
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Nov 21, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.2766delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2766, causing a translational frameshift with a predicted alternate stop codon (p.V923Lfs*77). This mutation has been detected in several patients, particularly of South Asian ancestry, with early-onset and/or triple-negative breast cancer (Ho GH et al. Cancer. 2000 Aug;89:811-6; Liede A et al. Am. J. Hum. Genet. 2002 Sep;71:595-606; Robertson L et al. Br J Cancer. 2012 Mar 13;106(6):1234-8; Donenberg T et al. Breast Cancer Res Treat. 2016 Aug;159(1):131-8). Of note, this mutation is also designated as 2885delA in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
not provided Pathogenic:1
Nov 08, 2022
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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2885delA; This variant is associated with the following publications: (PMID: 10951344, 26221963, 24578176, 27469594, 22333603, 21702907, 12181777, 12188064, 26315209, 20104584, 34657373, 33646313, 12442265, 29470806, 29446198, 31853058) -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Dec 04, 2024
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.Val923Leufs*77) 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: 10951344, 22333603, 26221963). ClinVar contains an entry for this variant (Variation ID: 54677). For these reasons, this variant has been classified as Pathogenic. -