chr17-43049181-C-T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5346G>A(p.Trp1782*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007294.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Fanconi anemia, complementation group SInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- pancreatic cancer, susceptibility to, 4Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727216 show subpopulations
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:9
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Variant allele predicted to encode a truncated non-functional protein. -
The c.5346G>A (p.Trp1782*) variant in the BRCA1 gene creates an premature translation termination codon. It is expected to result in an absent or disrupted protein product. This variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 9362443, 11773283, 12673801, 12960223, 16287141, 16683254, 18489799, 19949876, 25330149, 32824581). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). This variant is reported in ClinVar (ID: 37658). Truncating variants in BRCA1 are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore the c.5346G>A (p.Trp1782*) variant of the BRCA1 gene is classified as pathogenic. -
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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Hereditary breast ovarian cancer syndrome Pathogenic:4
This sequence change creates a premature translational stop signal (p.Trp1782*) 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 personal or family history of breast and/or ovarian cancer (PMID: 9362443, 12673801, 12960223, 16683254, 18489799, 19949876, 25330149). ClinVar contains an entry for this variant (Variation ID: 37658). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: The variant, BRCA1 c.5346G>A (p.Trp1782X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 277192 control chromosomes (gnomAD). The variant, c.5346G>A has been reported in the literature in multiple individuals affected with ovarian cancer, breast cancer Hereditary Breast and Ovarian Cancer and high risk patients with family history of HBOC (Example: Geisler_2002, Reedy_2002, Kroiss_2005, Pennington_2013). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports experimental evidence evaluating an impact on protein function and showed a damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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The p.Trp1782X (c.5346G>A) variant in BRCA1 has been reported in 15 individuals with BRCA1-associated cancers (Breast cancer information core (BIC) database, Ma chackova 2008, Sobczak 1997) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1782, which is predicted to lead to a truncated or absent protein. Heterozygous loss of func tion of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). Additionally, the p.Trp1782X variant was classified a s Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA Expert Panel (S CV000300246.2). In summary, this variant meets criteria to be classified as path ogenic for HBOC in an autosomal dominant manner based upon its predicted impact to the protein, absence from controls, and multiple reports in affected individu als. -
not provided Pathogenic:3
The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. -
Nonsense 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; Identified in patients with a personal or family history consistent with pathogenic variants in this gene in published literature (Sobczak 1997, Geisler 2002, Kroiss 2005, Machackova 2008); Published functional studies demonstrate a damaging effect: impaired cell survival (Findlay 2018); 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 5465G>A; This variant is associated with the following publications: (PMID: 10788334, 11773283, 25948282, 9362443, 18489799, 12960223, 19949876, 16287141, 12673801, 16267036, 26843898, 25330149, 28588062, 30209399, 32885271, 29446198, 33674644) -
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Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 21 of the BRCA1 gene, creating a 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. -
The p.W1782* pathogenic mutation (also known as c.5346G>A), located in coding exon 20 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5346. This changes the amino acid from a tryptophan to a stop codon within coding exon 20. This mutation has been reported in Polish and Czech families diagnosed with breast and/or ovarian cancer (Sobczak K et al. Oncogene. 1997 Oct;15:1773-9; Machackova E et al. BMC Cancer. 2008 May;8:140; Rogoa-Janiszewska E et al. Cancers (Basel). 2020 Aug;12:). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). Of note, this alteration is also designated as 5465G>A in some 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. -
Malignant tumor of breast Pathogenic:1
The BRCA1 p.Trp1782* variant was identified in 5 of 62980 proband chromosomes (frequency: 0.00008) from individuals or families with breast or ovarian cancer (Domagala 2015, Machackova 2008, Rebbeck 2018, Sobczak 1997). The variant was also identified in dbSNP (ID: rs80357284 as "With Pathogenic allele"), ClinVar (classified as pathogenic by ENIGMA, GeneDx, Counsyl, Ambry Genetics, Color Genomics, SCRP, BIC, and five other clinical laboratories), COGR, LOVD 3.0 (6x as pathogenic), UMD-LSDB (3x as causal), BIC Database (13x as clinically important), and ARUP Laboratories database (as definitely pathogenic). The variant was not identified in Cosmic, MutDB, Zhejiang University databases, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). However, the p.Trp1782* variant leads to a premature stop codon at position 1782, which is predicted to lead to 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at