Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP3PP5
The NM_007294.4(BRCA1):c.442C>T(p.Gln148*) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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 12 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;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
Variant 17-43099880-G-A is Pathogenic according to our data. Variant chr17-43099880-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 232203.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=4, Pathogenic=1}.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 561C>T; This variant is associated with the following publications: (PMID: 31131967) -
Mar 14, 2023
Revvity Omics, Revvity
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.Q148* variant (also known as c.442C>T), located in coding exon 6 of the BRCA1 gene, results from a C to T substitution at nucleotide position 442. This changes the amino acid from a glutamine to a stop codon within coding exon 6. RNA studies have shown that there is significant use of an alternative splice acceptor site at the beginning of coding exon 6 that would remove this alteration from the final transcript and result in a potentially functional protein (Ambry internal data; Colombo M et al. Hum Mol Genet. 2014 Jul 15;23(14):3666-80; Davy G et al. Eur J Hum Genet. 2017 Oct; 25(10): 1147–1154). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Mar 14, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant changes 1 nucleotide in exon 7 of the BRCA1 gene, creating a premature translation stop signal in the first codon of exon 7. The variant transcript is expected to undergo nonsense-mediated decay, resulting in an absent or non-functional protein product. There is a naturally occurring alternate transcript lacking the first 3 bp of exon 7 that may account for approximately one-third of total BRCA1 transcripts in normal tissues (PMID: 24569164, 28905878, 32133419). Because this truncation variant falls within the first 3 bp of exon 7, there is a possibility that the alternative splicing product could ameliorate the deleterious impact of this variant. However, this hypothesis has not been investigated in published functional studies. This variant has been detected in individuals with BRCA1-associated clinical features, as well as in unaffected individuals (communication with external laboratories). This variant has been observed in one family, and a multifactorial analysis based on co-occurrence with other pathogenic variant(s) and family history was not conclusive about the pathogenicity of this variant (PMID: 31131967). 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. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Dec 01, 2011
Sharing Clinical Reports Project (SCRP)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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not specified Uncertain:1
Dec 02, 2024
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.442C>T (p.Gln148X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. As the variant alters the first coding nucleotide (c.442) of exon 7 (also known as exon 8) located adjacent to the splice acceptor sequence, several computational tools predict a significant impact on normal splicing: Two predict the variant weakens the canonical 3' splicing acceptor site. Three predict the variant weakens the adjacent cryptic exonic alternate 3' acceptor site following nucleotide c.444. Internal RNA analysis (partner laboratory) confirms that there is expression of a naturally occurring isoform due to activation of a cryptic splice site 3 nucleotides upstream of the natural splice site. This can potentially rescue the effect of this variant due to an in-frame skipping of Gln148 amino acid residue. This observation is seen in carriers and controls. The variant was absent in 251404 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.442C>T has been reported in the literature in at-least one individual undergoing multigene panel analysis (example, Lilyquist_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28888541, 20232141, 16551709). ClinVar contains an entry for this variant (Variation ID: 232203). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Aug 28, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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. RNA studies show that the effect of this premature translational stop signal can be potentially rescued by a naturally-occurring isoform that results in skipping of the last amino acid residue of exon 7 (also known as exon 8), but is expected to preserve the integrity of the reading-frame (PMID: 28905878, 24569164, Invitae). ClinVar contains an entry for this variant (Variation ID: 232203). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 28888541). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln148*) 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). However, RNA analysis indicates that alternative usage of a cryptic splice site in exon 7, which results in the in-frame skipping of Gln148 amino acid residue, may functionally rescue this variant. -