chr17-43115729-C-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001407841.1(BRCA1):c.-8+1G>C 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 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Pathogenic:1
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 44 of the BRCA1 protein (p.Cys44Ser). For these reasons, this variant has been classified as Pathogenic. 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: 16403807, 20103620, 21725363, 21922593, 21990134, 23161852, 27272900). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 868170). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 18182601, 18500671, 19543972, 20104584, 35858847). This variant is not present in population databases (gnomAD no frequency). -
Breast-ovarian cancer, familial, susceptibility to, 1 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at