Submissions for variant NM_007294.4(BRCA1):c.5291T>C (p.Leu1764Pro)

dbSNP: rs80357281

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112604	SCV000244395	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.99
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112604	SCV000326250	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509995	SCV000607979	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-02-17	criteria provided, single submitter	clinical testing	The p.L1764P variant (also known as c.5291T>C), located in coding exon 19 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5291. The leucine at codon 1764 is replaced by proline, an amino acid with similar properties. The Leu1764 residue is deeply buried in the hydrophobic core of the highly conserved BRCT domain and as such, thermodynamic stability assays indicate that p.L1764P has a destabilizing effect (Rowling PJ et al. J Biol Chem. 2010 Jun; 285(26):20080-7). Functional studies including c-DNA complementation, homologous recombination, yeast-based assays, nuclear localization and solubility assays, and transcription activation assays have all demonstrated deficient function (Carvalho MA et al. Cancer Res. 2007 Feb; 67(4):1494-501; Bouwman P et al. Cancer Discov. 2013 Oct; 3(10):1142-55; Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90; Woods NT et al. NPJ Genom Med 2016 Mar;1; Petitalot A et al. Mol. Cancer Res. 2019 01;17(1):54-69). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562(7726):217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588744	SCV000699234	pathogenic	Hereditary breast ovarian cancer syndrome	2017-01-31	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.5291T>C (p.Leu1764Pro) variant located in the BRCT domain (via InterPro) involves the alteration of a conserved nucleotide, which 5/5 in silico tools predict a damaging outcome. Multiple functional studies have been performed that support these predictions. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications and databases. The variant of interest has been indicated to cause fold destabilization. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl	RCV000112604	SCV000786057	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-02-14	criteria provided, single submitter	clinical testing
Invitae	RCV000588744	SCV001578892	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1764 of the BRCA1 protein (p.Leu1764Pro). 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: 18824701, 26022348, 29446198, 30257646; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55510). 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: 17305420, 17308087, 20378548, 20516115, 23867111, 27272900, 30209399). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000112604	SCV004217014	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-12-19	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112604	SCV000145441	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112604	SCV001243050	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528204	SCV001739520	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528204	SCV001955181	pathogenic	not provided		no assertion criteria provided	clinical testing