Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1874_1877dupTAGT(p.Val627SerfsTer4) 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 1,461,816 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 17-43093653-T-TACTA is Pathogenic according to our data. Variant chr17-43093653-T-TACTA is described in ClinVar as [Pathogenic]. Clinvar id is 54376.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:9
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 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
Nov 15, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Oct 17, 2024
Department of Human Genetics, Hannover Medical School
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
ClinGen BRCA1 VCEP: PVS1, PM5_Strong -
Nov 03, 2014
Michigan Medical Genetics Laboratories, University of Michigan
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Feb 11, 2015
Institute of Human Genetics, Medical University Innsbruck
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
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
- -
Mar 02, 2020
BRCAlab, Lund University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
Jan 08, 2024
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant inserts 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.1877_1878insTAGT in the literature. 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 detected in at least four individuals affected with breast cancer (PMID: 12505256, 22970155, 25452441) and is detected in a breast cancer case-control meta-analysis in 2/60464 cases and absent in 53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001027). 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:4
Oct 14, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.Val627SerfsX4 variant in BRCA1 has been reported in at least 17 individuals with hereditary breast and/or ovarian cancer (HBOC; Kwong 2014, Balz 2002, Thomassen 2008, BIC database) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 627 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant HBOC. Additionally, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 54376). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4. -
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
- -
May 31, 2019
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.1874_1877dupTAGT (p.Val627SerfsX4) 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 251314 control chromosomes. c.1874_1877dupTAGT has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Balz_2002, Thomassen_2008, Kwong_2012, Couch_2015, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories and one expert panel (ENIGMA)(evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Dec 24, 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.Val627Serfs*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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and an individual affected with breast and/or ovarian cancer (PMID: 12505256, 22970155). This variant is also known as 1996insTAGT. ClinVar contains an entry for this variant (Variation ID: 54376). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
Jun 16, 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 several individuals with personal and/or family histories consistent with hereditary breast and/or ovarian cancer (Balz et al., 2002; Thomassen et al., 2008; Bellacosa et al., 2010; Kwong et al., 2012); 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 1877_1878insTAGT, 1878_1879insTAGT, 1997insTAGT, and 1996insTAGT; This variant is associated with the following publications: (PMID: 21702907, 16267036, 18465347, 28888541, 12505256, 20051372, 27157322, 22970155, 33087929, 29446198) -
Dec 15, 2014
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant inserts 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.1877_1878insTAGT in the literature. 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 detected in at least four individuals affected with breast cancer (PMID: 12505256, 22970155, 25452441) and is detected in a breast cancer case-control meta-analysis in 2/60466 cases and absent in 53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001027). 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. -
May 30, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.1874_1877dupTAGT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of TAGT at nucleotide position 1874, causing a translational frameshift with a predicted alternate stop codon (p.V627Sfs*4). This alteration has been previously identified in individuals with early-onset breast cancer (Balz V et al. Cancer Genet. Cytogenet. 2002 Oct;138:120-7; Bellacosa A et al. Cancer Prev. Res. (Phila.) 2010 Jan;3:48-61). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration has been denoted as 1996insTAGT and 1997insTAGT in the 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. -
Ovarian neoplasm Pathogenic:1
Dec 01, 2018
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne