Submissions for variant NM_007294.4(BRCA1):c.5056C>T (p.His1686Tyr)

dbSNP: rs1555579648

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637812	SCV000759291	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-22	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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.His1686 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12496477, 18757339, 23867111, 25452441, 30209399). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). 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: 531444). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1686 of the BRCA1 protein (p.His1686Tyr).
Fulgent Genetics, Fulgent Genetics	RCV000765358	SCV000896623	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001186735	SCV001353312	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces a conserved histidine with tyrosine at codon 1686 in the BRCT domain of the BRCA1 protein (PMID: 15133503, 18757339). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impacts BRCA1 function in haploid cell proliferation in the presence and absence of PARP inhibitor and in a homology-directed DNA repair assay (PMID: 30209399, 31467430). To our knowledge, this variant has not been reported in individuals affected with BRCA1-related disorders in the literature. Different missense variants at this codon, p.His1686Gln and p.His1686Arg, have been reported as disease-causing in ClinVar (variation ID: 55366, 183179). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001076299	SCV004817599	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces a conserved histidine with tyrosine at codon 1686 in the BRCT domain of the BRCA1 protein (PMID: 15133503, 18757339). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impacts BRCA1 function in haploid cell proliferation in the presence and absence of PARP inhibitor and in a homology-directed DNA repair assay (PMID: 30209399, 31467430). To our knowledge, this variant has not been reported in individuals affected with BRCA1-related disorders in the literature. Different missense variants at this codon, p.His1686Gln and p.His1686Arg, have been reported as disease-causing in ClinVar (variation ID: 55366, 183179). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Brotman Baty Institute, University of Washington	RCV001076299	SCV001242019	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro