Submissions for variant NM_007294.4(BRCA1):c.3250C>A (p.Leu1084Ile)

gnomAD frequency: 0.00001  dbSNP: rs879254009

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236406	SCV000293154	uncertain significance	not provided	2015-10-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.3250C>A at the cDNA level, p.Leu1084Ile (L1084I) at the protein level, and results in the change of a Leucine to an Isoleucine (CTT>ATT). Using alternate nomenclature, this variant would be defined as BRCA1 3369C>A. This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. BRCA1 Leu1084Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Leu1084Ile occurs at a position that is not conserved and is not located in a known functional domain (UniProt). 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 Leu1084Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531493	SCV000635891	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-05	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1084 of the BRCA1 protein (p.Leu1084Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 245941). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001180869	SCV001345911	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-07	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 1084 of the BRCA1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250504 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001180869	SCV002612425	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	The p.L1084I variant (also known as c.3250C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 3250. The leucine at codon 1084 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001180869	SCV003848964	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).