17-43115729-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001407841.1(BRCA1):c.-8+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_001407841.1 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5Uncertain:1Other:1
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IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 -
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not provided Pathogenic:3
Published functional studies demonstrate a damaging effect: reduced cellular proliferation, nuclear localization, and E3 ubiquitin ligase activity, as well as an inability to form a functional heterodimer with BARD1 (Brzovic et al., 2003; Morris et al., 2006; Millot et al., 2011; Starita et al., 2015); in addition, colony size, spot formation, and yeast localization assays of this variant also demonstrated a pathogenic effect (Thouvenot et al., 2016); A multifactorial model strongly predicted this variant to be deleterious (Lindor et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, including an individual with early-onset, triple negative disease and family history of bilateral breast cancer (Sweet et al., 2010; Sun et al., 2017); Also known as 250G>A; This variant is associated with the following publications: (PMID: 16403807, 12732733, 30209399, 24489791, 16267036, 24312913, 25823446, 27272900, 28724667, 30702160, 31825140, 33087888, 29446198, 21922593, 21990134, 8944023, 20104584, 24389207, 19543972) -
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The BRCA1 c.131G>A (p.Cys44Tyr) variant has been reported in the published literature in individuals with ovarian cancer (PMID: 36367610 (2023), 31825140 (2019)) and breast cancer (PMID: 27083775 (2016)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 21922593 (2011), 25823446 (2015), 27272900 (2016), 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.C44Y variant (also known as c.131G>A), located in coding exon 2 of the BRCA1 gene, results from a G to A substitution at nucleotide position 131. The cysteine at codon 44 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration, along with another alteration, p.C44S, at the same position, has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8; Lindor NM et al. Hum. Mutat., 2012 Jan;33:8-21). This alteration was shown to disrupt the function of the protein in multiple functional studies using different assays (Millot GA et al. Hum. Mutat., 2011 Dec;32:1470-80; Starita LM et al. Genetics, 2015 Jun;200:413-22; Thouvenot P et al. PLoS Genet., 2016 Jun;12:e1006096). In addition, a recent study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562(7726):217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 44 of the BRCA1 protein (p.Cys44Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 19543972, 27083775). ClinVar contains an entry for this variant (Variation ID: 54199). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 21922593, 27272900). This variant disrupts the p.Cys44 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19543972, 21990134, 27272900). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at