Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.112_113del(p.Lys38ValfsTer2) 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. K38K) has been classified as 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
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PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
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PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43115746-CTT-C is Pathogenic according to our data. Variant chr17-43115746-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 54141.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115746-CTT-C is described in Lovd as [Pathogenic]. Variant chr17-43115746-CTT-C is described in Lovd as [Pathogenic].
This variant deletes 2 nucleotides in exon 3 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 individuals and families affected with breast and/or ovarian cancer (PMID: 8533757, 9145677, 11844822, 14760071, 21080930), and has been identified in 4 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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
clinical testing
Ambry Genetics
Jan 06, 2021
The c.112_113delAA pathogenic mutation, located in coding exon 2 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 112 to 113, causing a translational frameshift with a predicted alternate stop codon (p.K38Vfs*2). This mutation has been reported in multiple HBOC families (Friedman LS et al. Am. J. Hum. Genet. 1995 Dec;57:1284-97; Couch FJ et al. N. Engl. J. Med. 1997 May;336:1409-15; Shih HA et al. J. Clin. Oncol. 2002 Feb;20:994-9). Of note, this mutation may be referred to as 230delAA or 231delAA in some literature. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
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
Invitae
Dec 27, 2023
This sequence change creates a premature translational stop signal (p.Lys38Valfs*2) 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: 8533757, 9145677, 11844822, 14760071, 21080930). This variant is also known as c.230delAA and c.231delAA. ClinVar contains an entry for this variant (Variation ID: 54141). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano