Submissions for variant NM_007294.4(BRCA1):c.5072C>A (p.Thr1691Lys)

dbSNP: rs80357034

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000048760	SCV000076773	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 1691 of the BRCA1 protein (p.Thr1691Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 22277901, 26757417, 29263802, 29752822, 32072338, 32091409). This variant is also known as 5191C>A. ClinVar contains an entry for this variant (Variation ID: 37627). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 22277901, 28781887, 30209399). 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.
GeneDx	RCV000485950	SCV000568400	likely pathogenic	not provided	2018-11-02	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5072C>A at the cDNA level, p.Thr1691Lys (T1691K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). Using alternate nomenclature, this variant has been previously published as BRCA1 5191C>A. This variant was observed in several women with breast and/or ovarian cancer (Lin 2011, Kuo 2012, Wong 2015, Ng 2016, Chirasophon 2017). In addition, multiple functional studies have demonstrated this variant to have a severe impact on transactivation, protease sensitivity, binding activity and sensitivity, nuclear spot formation, decreased nuclear localization and absence of growth inhibition (Lee 2010, Kuo 2012, Thouvenot 2016, Woods 2016). BRCA1 Thr1691Lys was not observed in large population cohorts (Lek 2016). This variant is located in the BRCT1 domain and within a region known to interact with multiple other proteins (Paul 2014, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider BRCA1 Thr1691Lys to be a likely pathogenic variant.
Ambry Genetics	RCV000574915	SCV000660999	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	The p.T1691K variant (also known as c.5072C>A), located in coding exon 15 of the BRCA1 gene, results from a C to A substitution at nucleotide position 5072. The threonine at codon 1691 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Kuo WH et al. J. Hum. Genet., 2012 Feb;57:130-8; Wong ES et al. PLoS ONE, 2015 Jul;10:e0134408; Ng PS et al. Clin. Genet., 2016 Oct;90:315-23). Functional data show that this alteration is defective in many assays including two transcription activation assays, a protein binding assay, a binding specificity assay and a homology-directed repair assay (Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Kuo WH et al. J. Hum. Genet., 2012 Feb;57:130-8; Woods NT et al. NPJ Genom Med, 2016 Mar;1; Ambry internal data). Based on published literature and internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Williams RS et al. Nat. Struct. Biol., 2001 Oct;8:838-42; Thouvenot P et al. J. Cell. Sci., 2016 12;129:4366-4378). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000574915	SCV000908995	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with lysine at codon 1691 of the BRCA1 protein. 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 reported that this variant impacts BRCA1 function in transcription activation, haploid cell proliferation, yeast growth inhibition, protease sensitivity, peptide binding and subcellular localization assays (PMID: 20516115, 22277901, 27802165, 28781887, 28961279, 30209399). This variant has been reported in at least six individuals affected with breast and ovarian cancer (PMID: 22277901, 26221963, 26757417, 28188963, 33471991; Leiden Open Variation Database DB-ID BRCA1_000510; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031208	SCV000053808	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2008-11-20	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031208	SCV000145285	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031208	SCV001244014	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Center for Precision Medicine, Meizhou People's Hospital	RCV002250478	SCV002520769	likely pathogenic	Familial cancer of breast		no assertion criteria provided	literature only