Submissions for variant NM_007294.4(BRCA1):c.5254G>A (p.Ala1752Thr)

dbSNP: rs80357074

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001190129	SCV001357547	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1752 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in transcription activation, homology-directed DNA repair and a haploid cell proliferation assays (PMID: 24845084, 30209399, 30257991). This variant has been reported in an individual affected with ovarian cancer who underwent testing for the BRCA1 and BRCA2 genes (PMID: 33078592, 34063308). 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.
Invitae	RCV001222121	SCV001394205	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1752 of the BRCA1 protein (p.Ala1752Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 33078592). ClinVar contains an entry for this variant (Variation ID: 96944). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 24845084, 28781887, 30209399, 30257991). 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.
GeneDx	RCV001567559	SCV001791268	likely pathogenic	not provided	2019-05-24	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28781887, 30209399, 30765603, 24845084, 30257991)
Ambry Genetics	RCV001190129	SCV002643325	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-09-29	criteria provided, single submitter	clinical testing	The p.A1752T variant (also known as c.5254G>A), located in coding exon 18 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5254. The alanine at codon 1752 is replaced by threonine, an amino acid with similar properties. Multiple functional studies have show this alteration to be non-functional (Carvalho RS et al. PLoS One, 2014 May;9:e97766; Findlay GM et al. Nature, 2018 10;562:217-222; Fernandes VC et al. J Biol Chem, 2019 04;294:5980-5992; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69). This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Ha HI et al. J Gynecol Oncol, 2020 Nov;31:e83; Park KS et al. Cancers (Basel), 2021 May;13). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000083065	SCV000115139	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2009-02-07	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000083065	SCV001242479	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro