Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4612C>T(p.Gln1538*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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.
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 17-43074394-G-A is Pathogenic according to our data. Variant chr17-43074394-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55239.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074394-G-A is described in Lovd as [Pathogenic]. Variant chr17-43074394-G-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
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. -
May 01, 2012
Sharing Clinical Reports Project (SCRP)
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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Oct 22, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Pathogenic:2
May 02, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant causes the premature termination of BRCA1 protein synthesis. It has been reported in in affected individuals with breast and/or ovarian cancer in the published literature (PMIDs: 9452076 (1998), 11920621 (2002), 25151137 (2015), 29339979 (2018) and 29470806 (2018)). Based on the available information, this variant is classified as pathogenic. -
Sep 28, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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; 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 4731C>T; This variant is associated with the following publications: (PMID: 21720365, 9452076, 11920621, 25525159, 26187060, 24578176, 25151137, 27221827, 19298662, 29339979, 30787465, 29470806, 31214711, 32410793, 29446198, 34917121, 30720243, 31825140, 30322717, 33948387) -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant changes 1 nucleotide in exon 14 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. -
Mar 13, 2025
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.Q1538* pathogenic mutation (also known as c.4612C>T), located in coding exon 13 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4612. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This variant has been reported in multiple individuals and families with hereditary breast and ovarian cancer (HBOC) (Tartaglini E et al. Hum. Mutat., 1998;Suppl 1:S163-6; De Leon Matsuda ML et al. Int. J. Cancer, 2002 Apr;98:596-603; Young SR et al. BMC Cancer, 2009 Mar;9:86; Guan Y et al. Fam Cancer, 2015 Mar;14:9-18; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Wang N et al. Chin J Cancer Res, 2020 Apr;32:149-162). Of note, this alteration is also designated as 4731C>T 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Feb 12, 2020
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.4612C>T (p.Gln1538X) 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. The variant was absent in 251362 control chromosomes (gnomAD). c.4612C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Rebbeck_2018, DeLeonMatsuda_2002, Singh_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) including one expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Jan 28, 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.Gln1538*) 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 clinical features of hereditary breast and ovarian cancer syndrome (PMID: 9452076, 11920621, 25151137, 29446198, 29470806). This variant is also known as 4731C>T. ClinVar contains an entry for this variant (Variation ID: 55239). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -