Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2_SupportingPM5PP3_ModeratePP5_Moderate
The NM_007294(BRCA1):c.5117G>T(p.Gly1706Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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. G1706A) has been classified as Benign.
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
GnomAD3 genomesCov.: 32
Submissions by phenotype
Hereditary breast ovarian cancer syndrome
|Likely pathogenic, criteria provided, single submitter||clinical testing||Invitae||Oct 13, 2022||This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1706 of the BRCA1 protein (p.Gly1706Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 868673). 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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). This variant disrupts the p.Gly1706 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10755399, 11979449, 12385650, 15689452, 15923272, 17262179, 17308087, 17924331, 20516115, 20727672, 22144684, 23867111, 25948282, 27272900, 27616075, 28781887, 29446198, 30209399, 30458859). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -|
Breast-ovarian cancer, familial, susceptibility to, 1
|not provided, no assertion provided||in vitro||Brotman Baty Institute, University of Washington||-||- -|
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