rs41293459
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5096G>T(p.Arg1699Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1699Q) has been classified as Pathogenic.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Uncertain:1Other:1
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This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30209399, 35196514]. -
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Hereditary breast ovarian cancer syndrome Pathogenic:1
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg1699 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11157798, 17308087, 17574969, 20516115, 21324516, 21356067, 21473589, 22889855, 23867111, 25472942). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 25748678). 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: 55398). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 10923033). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1699 of the BRCA1 protein (p.Arg1699Leu). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at