Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3705_3747dupCAATATACCTTCTCAGTCTACTAGGCATAGCACCGTTGCTACC(p.Glu1250fs) variant causes a frameshift, stop gained 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. T1249T) 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
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 17-43091783-C-CGGTAGCAACGGTGCTATGCCTAGTAGACTGAGAAGGTATATTG is Pathogenic according to our data. Variant chr17-43091783-C-CGGTAGCAACGGTGCTATGCCTAGTAGACTGAGAAGGTATATTG is described in ClinVar as [Pathogenic]. Clinvar id is 440468.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Dec 15, 2017
Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Nov 09, 2023
The c.3705_3747dup (p.Glu1250Glnfs*8) variant of the BRCA1 gene creates an premature translation termination codon. It is predicted to result in an absent or disrupted protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). ClinVar has an entry for this variant and it has been classified as pathogenic by the expert panel (ID: 440468). Truncating variants in BRCA1 gene are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore the c.3705_3747dup (p.Glu1250Glnfs*8) variant of the BRCA1 gene is classified as pathogenic. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Jan 25, 2018
- -
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Jul 18, 2016
- -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jan 04, 2016
Variant summary: This c.3705_3747dup43 variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 1250 and leads to a premature termination codon 8 amino acids downstream. It is predicted to cause a truncated or absent BRCA1 protein. Heterozygous loss-of-function due to mutations in this gene is an established disease mechanism in HBOC. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Glu1257fs). This variant was not found in approximately 121390 chromosomes from broad and large populations from ExAC. To our knowledge, this variant has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories. Taken together, this variant has currently been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Aug 02, 2023
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 440468). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1250Glnfs*8) 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). -
The c.3705_3747dup43 pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of CAATATACCTTCTCAGTCTACTAGGCATAGCACCGTTGCTACC at nucleotide position 3705, causing a translational frameshift with a predicted alternate stop codon (p.E1250Qfs*8). This variant is considered to be rare based on population 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. -