Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.895_896delGT(p.Val299ArgfsTer4) 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 1,461,874 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 17-43094634-TAC-T is Pathogenic according to our data. Variant chr17-43094634-TAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 55744.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094634-TAC-T is described in Lovd as [Pathogenic]. Variant chr17-43094634-TAC-T is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
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. -
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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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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Jan 20, 2023
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.Val299ArgfsX4 deletion variant was identified in 9 of 3242 proband chromosomes (frequency: 0.003) from individuals with breast or ovarian cancer (Couch 1997, Fong 2010, Hansa 2012, Kote-Jarai 2006, Martin 2001, Risch 2006). The variant was also identified in dbSNP (ID: rs80357670), HGMD, and the BIC database (2X as clinically important variant). The p.Val299ArgfsX4 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 299 and leads to a premature stop codon at position 303. 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. -
Breast and/or ovarian cancer Pathogenic:2
Sep 20, 2013
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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May 05, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Pathogenic:2
May 04, 2023
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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Couch et al., 1997; Martin et al., 2001; Soussi et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1014_1015delGT; This variant is associated with the following publications: (PMID: 11304778, 26681312, 9145677, 31528241, 29625052, 29922827, 26689913, 35710434, 32885271, 30720243) -
Jun 07, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The BRCA1 c.895_896del (p.Val299Argfs*4) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals and families with breast and/or ovarian cancer (PMIDs: 36451132 (2022), 36169650 (2022), 35710434 (2022), 29446198 (2018), 26681312 (2015), 11304778 (2001), and 9145677 (1997)). Based on the available information, this variant is classified as pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.895_896delGT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 895 to 896, causing a translational frameshift with a predicted alternate stop codon (p.V299Rfs*4). This mutation has been identified in multiple individuals and families affected with breast and ovarian cancer (Couch FJ et al. N. Engl. J. Med., 1997 May;336:1409-15; Liede A et al. Am. J. Hum. Genet., 2002 Sep;71:595-606; Hansa J et al. Asian Pac. J. Cancer Prev., 2012;13:5871-4; Susswein LR et al. Genet Med. 2016 Aug;18(8):823-832.). Of note, this alteration is also is also designated as 1014delGT and 1013delTG 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. -
Jan 10, 2023
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 been reported as 1014delGT and 1013delTG in at least four individuals affected with breast or ovarian cancer (PMID: 9145677, 12181777, 21324516, 22776961). This variant has been identified in 1/251288 chromosomes 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:2
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
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Nov 27, 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.Val299Argfs*4) 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 (rs80357670, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9145677, 26187060, 26681312). This variant is also known as c.1014delGT. ClinVar contains an entry for this variant (Variation ID: 55744). For these reasons, this variant has been classified as Pathogenic. -