Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000357654.9(BRCA1):c.4258C>T(p.Gln1420Ter) 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. Q1420Q) has been classified as Likely benign. 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 17-43082503-G-A is Pathogenic according to our data. Variant chr17-43082503-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55155.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43082503-G-A is described in Lovd as [Pathogenic]. Variant chr17-43082503-G-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8
Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Sep 08, 2016
Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Apr 24, 2013
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Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Jun 22, 1999
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Pathogenic, criteria provided, single submitter
research
Institute of Genomics, University of Tartu
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Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Mar 01, 2022
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Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
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Pathogenic, criteria provided, single submitter
clinical testing
GeneKor MSA
Jan 01, 2020
This variant is a single amino acid change from Glutamine to a Termination codon at amino acid residue 1420 of the BRCA1 gene. It is expected to result in a truncated, non-functional protein. This variant is also known as c.4377C>T in the literature has been reported in patients with breast and/or ovarian cancer (PMID: 18627636, 26306726). The mutation database ClinVar contains entries for this variant (Variation ID: 55155). -
The p.Q1420* pathogenic mutation (also known as c.4258C>T), located in coding exon 11 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4258. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation has been previously reported in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Minucci A et al. Expert Rev. Mol. Diagn. 2015 Aug;15:1383-403; Thirthagiri E et al. Breast Cancer Res. 2008 Jul;10:R59; Wen WX et al. J Med Genet, 2018 02;55:97-103; De Talhouet S et al. Sci Rep, 2020 04;10:7073; Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 4377C>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. -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Apr 18, 2022
This variant changes 1 nucleotide in exon 12 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 18627636, 26306726; doi:10.1515/tjb.2019.0424). 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. -
Pathogenic, criteria provided, single submitter
curation
Sema4, Sema4
Nov 22, 2021
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Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Feb 16, 2023
This sequence change creates a premature translational stop signal (p.Gln1420*) 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 and/or ovarian cancer (PMID: 18627636, 21120943, 26306726). This variant is also known as c.4377C>T. ClinVar contains an entry for this variant (Variation ID: 55155). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided
research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Jan 31, 2014
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Pathogenic, criteria provided, single submitter
clinical testing
Mendelics
Jul 02, 2018
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not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Jan 04, 2022
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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Thirthagiri 2008, Minucci 2015, Couch 2015); 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 4377C>T; This variant is associated with the following publications: (PMID: 9796975, 25452441, 25525159, 18627636, 26306726, 29446198, 32341426, 28993434, 30702160) -
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
May 04, 2021
This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals affected with breast or ovarian cancer in the published literature (PMIDs: 18627636 (2008) and 26306726 (2015)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic. -