Submissions for variant NM_007294.4(BRCA1):c.290C>G (p.Thr97Arg)

gnomAD frequency: 0.00001  dbSNP: rs431825393

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197536	SCV000254965	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-30	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 25823446, 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 96909). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 97 of the BRCA1 protein (p.Thr97Arg).
Ambry Genetics	RCV000217842	SCV000274180	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-08	criteria provided, single submitter	clinical testing	The p.T97R variant (also known as c.290C>G), located in coding exon 4 of the BRCA1 gene, results from a C to G substitution at nucleotide position 290. The threonine at codon 97 is replaced by arginine, an amino acid with similar properties. This alteration was partially functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222; Starita LM et al. Am J Hum Genet, 2018 10;103:498-508). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000083030	SCV000489325	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001575395	SCV001802379	uncertain significance	not provided	2023-02-06	criteria provided, single submitter	clinical testing	Published functional studies are inconclusive: partial reduction in BARD1 binding ability, ubiquitine ligase activity, and cell survival (Starita et al., 2015; Findlay et al., 2018); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 409C>G; This variant is associated with the following publications: (PMID: 30209399, 25823446, 30219179, 29884841, 24389207, 20104584, 32377563)
Sharing Clinical Reports Project (SCRP)	RCV000083030	SCV000115104	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000083030	SCV001238220	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro