Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1188del(p.Asp396GlufsTer14) 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 17-43094342-CA-C is Pathogenic according to our data. Variant chr17-43094342-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 54158.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094342-CA-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Oct 30, 2021
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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, criteria provided, single submitter
clinical testing
Molecular Endocrinology Laboratory, Christian Medical College
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not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Apr 09, 2015
This pathogenic variant is denoted BRCA1 c.1188delT at the cDNA level and p.Asp396GlufsX14 (D396EfsX14) at the protein level. The normal sequence with the bases that are deleted in brackets is CTGA[T]GACT. This deletion is also known as BRCA1 1307delT using alternate nomenclature. The deletion causes a frameshift, changing an Aspartic Acid to a Glutamic Acid at codon 396, and creating a premature stop codon at position 14 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.1188delT has been observed in at least one patient of Indian descent with a clinical history consistent with hereditary breast and/or ovarian cancer (Gajalakshmi 2007). we consider this variant to be pathogenic. -
The c.1188delT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1188, causing a translational frameshift with a predicted alternate stop codon (p.D396Efs*14). This mutation, designated as 1307delT, has been reported in an Indian proband diagnosed with breast cancer at age 43 years (Gajalakshmi P et al. Breast Cancer Res. Treat. 2007 Jan;101(1):3-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
BRCA1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided
clinical testing
PreventionGenetics, part of Exact Sciences
Jul 18, 2024
The BRCA1 c.1188delT variant is predicted to result in a frameshift and premature protein termination (p.Asp396Glufs*14). This variant has been reported in individuals with with Breast and/or ovarian cancer (Table S1; Singh et al 2018. PubMed ID: 29470806; Rashid MU et al 2019. PubMed ID: 31528241). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Mar 31, 2023
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54158). This variant is also known as c.1307delT. This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 17131039, 29470806). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp396Glufs*14) 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). -