chr17-43115726-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_001407889.1(BRCA1):c.-171A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001407889.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250502Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135398
GnomAD4 exome Cov.: 30
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3Benign:1Other:1
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This missense variant replaces lysine with threonine at codon 45 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies reported conflicting variant impact on BRCA1 function from loss of ubiquitin ligase activity (PMID: 16403807) to no impact on a haploid human cell proliferation assay (PMID: 30209399). This variant has been observed in an individual affected with unilateral breast cancer (PMID: 20104584) and an individual age 70 years or older without cancer (FLOSSIES database). This variant also has been reported in a multifactorial analysis with family history likelihood ratio for pathogenicity of 0.0387 (PMID: 31131967). This variant has been identified in 2/250502 chromosomes 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. -
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not provided Uncertain:1Benign:1
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Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20104584, 30209399, 21520273, 15235020, 16403807, 21523855, 000, 19543972, 16267036, 15385441, 25823446, 24489791, 33087888) -
Hereditary cancer-predisposing syndrome Benign:2
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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. -
not specified Benign:1
Variant summary: BRCA1 c.134A>C (p.Lys45Thr) results in a non-conservative amino acid change located in the Zinc finger, RING-type (IPR001841) and Zinc finger, C3HC4 RING-type (IPR018957) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 250502 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.134A>C has been reported in the literature (e.g. Borg 2010). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.26_26delC, p.Pro9Glnfs, BIC database), providing supporting evidence for a benign role. At least one functional study reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. In another in-vitro assay, this variant was shown to decrease the ubiquitin ligase activity (Morris_2006, Starita_2015). The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 20104584, 15235020, 21520273, 16403807, 25823446, 30209399). ClinVar contains an entry for this variant (Variation ID: 37402). Based on the evidence outlined above, the variant was classified as likely benign. -
Hereditary breast ovarian cancer syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at