Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_007294.4(BRCA1):c.5578dupC(p.His1860ProfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,468 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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 Uncertain_significance. Variant got 4 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0025 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant inserts 1 nucleotide in exon 23 of the BRCA1 gene, creating a frameshift in the last coding exon. This variant is not expected to trigger nonsense-mediated decay and it causes a frameshift after the BRCT domain (PMID: 11573086, 20516115, 30765603). This variant has been reported in an individual affected with ovarian cancer (PMID: 30322717) and the clinical history of five carriers has been calculated to a likelihood ratio for pathogenicity of 0.090 (PMID: 31853058). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Dec 29, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation
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Jan 25, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Uncertain:1
Jul 25, 2006
Sharing Clinical Reports Project (SCRP)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Aug 24, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Uncertain:2
Mar 13, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The BRCA1 c.5578dup (p.His1860Profs*20) variant disrupts the translation stop codon of the BRCA1 mRNA and is predicted to cause BRCA1 protein elongation. This variant has been reported in the published literature in an individual with ovarian cancer (PMID: 30322717 (2018)) and in an undiagnosed individual (PMID: 24784157 (2014)). A study based on personal and family histories of five index cases with this variant reported that this variant had high odds against pathogenicity (PMID: 31853058 (2020)). Additionally, a functional study suggests that the variant is not damaging to protein function (PMID: 31853058 (2020)). The frequency of this variant in the general population, 0.000004 (1/247040 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -
Jan 08, 2025
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Frameshift variant predicted to result in abnormal protein length as the last 4 amino acids are replaced with 19 different amino acids; Observed in an individual with epithelial ovarian cancer (PMID: 37718511); Logistical regression analysis used to predict carrier status based on personal and family history of cancer yielded 10:1 odds against pathogenicity (PMID: 31853058); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5697dup; This variant is associated with the following publications: (PMID: 24784157, 30322717, 10220405, 24389207, 10196224, 9738006, 9811458, 9926942, 9974970, 9159119, 11301010, 30765603, 37718511, 31853058, 31360874) -
not specified Uncertain:1
Aug 10, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.5578dupC (p.His1860ProfsX20) causes a frameshift which results in an extension of the protein. This variant is located in the last exon and is unlikely to trigger nonsense mediated decay, but is predicted to replace the last 4 amino acids including the termination codon with 19 amino acids ending at a newly created stop signal, lengthening the C-terminus of the protein. The variant allele was found at a frequency of 4e-06 in 247040 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5578dupC has been reported in the literature in an individual with Ovarian cancer undergoing multigene NGS panel testing (Carter_2018), as a reportable incidental variant in an individual tested by exome sequencing in the NIH Undiagnosed Diseases Program (Lawrence_2015), with a high odds against pathogenicity in 5 index cases tested by multigene panel testing (Li_2019), as a VUS in an individual with colorectal cancer (Toh_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported for this variant. A study performed in yeast suggests that amino acids from position 1855 of the protein to the C-terminal are dispensible for protein activation (Hayes_2000), however it is not clear how these findings would translate to human cells and additional functional studies are needed to substantiate these findings. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Jun 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change results in a frameshift in the BRCA1 gene (p.His1860Profs*20). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the BRCA1 protein and extend the protein by 15 additional amino acid residues. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This frameshift has been observed in individual(s) with colorectal cancer or ovarian tumor(s) (PMID: 30322717, 31360874). ClinVar contains an entry for this variant (Variation ID: 37683). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Fanconi anemia, complementation group S Uncertain:1
Jul 14, 2022
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: criteria provided, single submitter