Submissions for variant NM_007294.4(BRCA1):c.1534C>G (p.Leu512Val)

dbSNP: rs41286294

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130372	SCV000185226	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-06	criteria provided, single submitter	clinical testing	The p.L512V variant (also known as c.1534C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 1534. The leucine at codon 512 is replaced by valine, an amino acid with highly similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This alteration has been reported in a breast cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas, and was functional in a homology directed DNA repair (HDR) assay (Lu C et al. Nat Commun, 2015 Dec;6:10086). In one study, this exonic missense variant was predicted not to effect splicing using mini gene splicing assay (Anczuków O et al. Genes Chromosomes Cancer, 2008 May;47:418-26). This amino acid position is highly 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.
Invitae	RCV000198821	SCV000254957	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000758787	SCV000566052	uncertain significance	not provided	2016-03-30	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1534C>G at the cDNA level, p.Leu512Val (L512V) at the protein level, and results in the change of a Leucine to a Valine (CTT>GTT). Using alternate nomenclature, this variant would be defined as BRCA1 1653C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Leu512Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Leu512Val occurs at a position that is conserved across species and is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Leu512Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130372	SCV000682970	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000662675	SCV000785382	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758787	SCV000887626	uncertain significance	not provided	2021-07-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000758787	SCV001474332	uncertain significance	not provided	2020-06-15	criteria provided, single submitter	clinical testing	The BRCA1 c.1534C>G; p.Leu512Val variant (rs41286294) is reported in the literature in a cohort of individuals affected with cancer, though it was not demonstrated to be disease-causing (Lu 2015). This variant is found on a single chromosome in the Genome Aggregation Database (1/250832 alleles), indicating it is not a common polymorphism. The leucine at codon 512 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, in an assay of homology-directed repair function, the p.Leu512Val variant exhibited activity comparable to wildtype BRCA1 (Lu 2015). Due to limited information, the clinical significance of the p.Leu512Val variant is uncertain at this time. References: Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015;6:10086.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130372	SCV003851229	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
CeGaT Center for Human Genetics Tuebingen	RCV000758787	SCV003917929	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	BRCA1: BP1, BS3:Supporting