Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3642_3643delGA(p.Asn1215LeufsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 17-43091887-TTC-T is Pathogenic according to our data. Variant chr17-43091887-TTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 54950.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091887-TTC-T is described in Lovd as [Pathogenic]. Variant chr17-43091887-TTC-T is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3
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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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. -
Jul 19, 2006
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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not provided Pathogenic:2
Sep 24, 2018
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This deletion of two nucleotides in BRCA1 is denoted c.3642_3643delGA at the cDNA level and p.Asn1215LeufsX3 (N1215LfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAGA[delGA]ACTT. The deletion causes a frameshift which changes an Asparagine to a Leucine at codon 1215, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.3642_3643delGA, also reported as BRCA1 3761_3762delGA using alternate nomenclature, has been reported in association with breast and ovarian cancer (Machackova 2001, Foretova 2004). We consider this variant to be pathogenic. -
Aug 11, 2017
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:2
Jul 16, 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.Asn1215Leufs*3) 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: 11748848, 18489799). This variant is also known as 3761_3762delGA. ClinVar contains an entry for this variant (Variation ID: 54950). For these reasons, this variant has been classified as Pathogenic. -
Sep 26, 2018
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.3642_3643delGA (p.Asn1215LeufsX3) 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 246070 control chromosomes (gnomAD). The variant, c.3642_3643delGA, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Machackova_2001, Machackova_2008). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Breast and/or ovarian cancer Pathogenic:1
Jun 11, 2019
CZECANCA consortium
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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BRCA1-related cancer predisposition Pathogenic:1
Jul 10, 2024
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant deletes 2 nucleotides in exon 10 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 reported in at least 3 unrelated individuals affected with breast or ovarian cancer and at 10 suspected hereditary breast and ovarian cancer families (PMID: 11748848, 18489799, 31341520, 31409081). A multifactorial analysis has reported a likelihood ratio (LR) for pathogenicity based on health history of log(LR) = 0.2028528005 (PMID: 31853058). 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. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.3642_3643delGA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3642 to 3643, causing a translational frameshift with a predicted alternate stop codon (p.N1215Lfs*3). This mutation (designated as 3761-3762delGA) has previously been reported in a family with three relatives affected with breast and/or ovarian cancer (Machackova E et al. Hum. Mutat. 2001 Dec; 18(6):545). 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. -