17-43092293-A-G
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_007294.4(BRCA1):c.3238T>C(p.Leu1080Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Consequence
NM_007294.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250454Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135338
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461668Hom.: 0 Cov.: 39 AF XY: 0.0000124 AC XY: 9AN XY: 727124
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74314
ClinVar
Submissions by phenotype
not provided Benign:3
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The BRCA1 p.Leu1080Leu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site; in addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified in UMD (2X as an unclassified variant) and in the Exome Aggregation Consortium (ExAC) database in 3/11574 Latino alleles, 2/16506 South Asian alleles, and in 1/908 alleles of “other” ethnic origin; this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was not identified in the literature, nor was it identified any of the other databases searched, including: dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, ClinVar, GeneInsight VariantWire, and BIC. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. -
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Hereditary cancer-predisposing syndrome Benign:3
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. -
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Breast-ovarian cancer, familial, susceptibility to, 1 Benign:2
Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). -
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not specified Benign:1
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BRCA1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
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