Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3858_3861delTGAG(p.Ser1286ArgfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,866 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 17-43091669-CCTCA-C is Pathogenic according to our data. Variant chr17-43091669-CCTCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 37553.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091669-CCTCA-C is described in Lovd as [Pathogenic]. Variant chr17-43091669-CCTCA-C is described in Lovd as [Pathogenic].
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.3858_3861delTGAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 3858 through 3861, causing a translational frameshift with a predicted alternate stop codon (p.S1286Rfs*20). This mutation has been identified in multiple high-risk breast/ovarian cancer families (Gonzalez-Hormazabal P et al, Breast Cancer Res. Treat. 2011 Apr; 126(3):705-16; Ang P et al, Cancer Epidemiol. Biomarkers Prev. 2007 Nov; 16(11):2276-84; Khoo US et al, Hum. Mutat. 2000 Jul; 16(1):88-9). Of note, this alteration is also designated as 3977del4 and 3976_3979delGTGA in 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. -
Jan 15, 2020
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant deletes 4 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 identified in 2/251128 chromosomes 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:2
Dec 13, 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.Ser1286Argfs*20) 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 present in population databases (rs80357889, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast cancer/ovarian cancer (PMID: 10874312, 20859677, 26187060). This variant is also known as 3976-3979delGTGA and 3977del4. ClinVar contains an entry for this variant (Variation ID: 37553). For these reasons, this variant has been classified as Pathogenic. -
Mar 07, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: The BRCA1 c.3858_3861delTGAG (p.Ser1286Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. c.3868A>T (p.Lys1290X), c.3869_3870delAA (p.Lys1290fs), and c.3893C>A (p.Ser1298X; c.3904G>T)). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121396 control chromosomes (ExAC). Multiple publications have cited the variant in affected individuals (BrC, OvC, HBOC). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
not provided Pathogenic:1
May 28, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals with breast cancer in the published literature (PMID: 31825140 (2019), 25236687 (2015), 20859677 (2011), and 18006916 (2007)). Based on the available information, this variant is classified as pathogenic. -