Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4936delG(p.Val1646SerfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,888 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 17-43070977-AC-A is Pathogenic according to our data. Variant chr17-43070977-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 55322.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43070977-AC-A is described in Lovd as [Pathogenic]. Variant chr17-43070977-AC-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3
Jun 21, 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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Apr 22, 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:3
Jan 12, 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.Val1646Serfs*12) 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 (rs80357705, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11710890, 25476495). This variant is also known as 5055 delG; Stop 1657. ClinVar contains an entry for this variant (Variation ID: 55322). For these reasons, this variant has been classified as Pathogenic. -
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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Jul 05, 2024
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.4936delG (p.Val1646SerfsX12) 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 allele was found at a frequency of 8e-06 in 251230 control chromosomes. c.4936delG has been reported in the literature in individuals affected with Hereditary Breast or Ovarian Cancer (e.g. King_2001, Harter_2017). The following publications have been ascertained in the context of this evaluation (PMID: 29053726, 11710890). ClinVar contains an entry for this variant (Variation ID: 55322). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
Sep 24, 2024
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; 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 5055delG; This variant is associated with the following publications: (PMID: 15217508, 16267036, 12112655, 29053726, 28873162, 29922827, 30040829, 11710890, 22430266, 21702907, 25476495, 21156238, 17064299, 28398198, 30014164, 33054725, 30787465, 37718511, 34620496) -
Jun 12, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The BRCA1 c.4936del (p.Val1646Serfs*12) 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 with breast cancer (PMID: 12112655 (2002), 25476495 (2015), 30014164 (2018), 33054725 (2020)), ovarian cancer (PMID: 30040829 (2018)), and an unspecified advanced cancer (PMID: 28873162 (2017)). The frequency of this variant in the general population, 0.000008 (2/251230 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.4936delG pathogenic mutation, located in coding exon 14 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 4936, causing a translational frameshift with a predicted alternate stop codon (p.V1646Sfs*12). This mutation has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (King MC et al. JAMA, 2001 Nov;286:2251-6; Yazici H et al. Hum. Mutat., 2002 Jul;20:28-34; Lindeman GJ et al. Breast Cancer Res., 2004 Jun;6:R401-7). This mutation was also a non-founder mutation identified in individuals of full or partial Ashkenazi Jewish ancestry (Rosenthal E et al. Breast Cancer Res. Treat., 2015 Jan;149:223-7; Rosenthal E et al. Breast Cancer Res Treat, 2015 May;151:233; Barnes-Kedar I et al. Breast Cancer Res Treat, 2018 Nov;172:151-157). Of note, this alteration is also designated as 5055delG 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 15, 2020
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant deletes 1 nucleotide in exon 15 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 identified in 2/251230 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. -
Ovarian neoplasm Pathogenic:1
Dec 01, 2018
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
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Breast carcinoma Pathogenic:1
Aug 09, 2021
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences