Submissions for variant NM_007294.4(BRCA1):c.2992C>G (p.Leu998Val)

dbSNP: rs876659077

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217975	SCV000275099	uncertain significance	Hereditary cancer-predisposing syndrome	2015-04-14	criteria provided, single submitter	clinical testing	The p.L998V variant (also known as c.2992C>G and 3111C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 2992. The leucine at codon 998 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6501 samples (13002 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 105000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.L998V remains unclear.
Invitae	RCV000462913	SCV000549412	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 998 of the BRCA1 protein (p.Leu998Val). This variant is not present in population databases (gnomAD no frequency). 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: 231296). 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. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000217975	SCV003849205	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).
GeneDx	RCV003223627	SCV003919707	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3111C>G; This variant is associated with the following publications: (PMID: 15343273)