Submissions for variant NM_007294.4(BRCA1):c.5512G>T (p.Val1838Leu)

dbSNP: rs730881501

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164331	SCV000214962	uncertain significance	Hereditary cancer-predisposing syndrome	2014-06-02	criteria provided, single submitter	clinical testing	The p.V1838L variant (also known as c.5512G>T or 5631G>T), located in coding exon 22 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5512. The valine at codon 1838 is replaced by leucine, 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. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 42000 alleles tested) in our clinical cohort (includes this individual). Based on protein sequence alignment, this amino acid position is highly 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.V1838L remains unclear.
Invitae	RCV000540103	SCV000636052	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-02-19	criteria provided, single submitter	clinical testing	Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. This variant disrupts the p.Val1838 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18375895, 20516115, 21990134, 27272900). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1838 of the BRCA1 protein (p.Val1838Leu). 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: 184981).
Color Diagnostics, LLC DBA Color Health	RCV000164331	SCV000683330	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-14	criteria provided, single submitter	clinical testing
Brotman Baty Institute, University of Washington	RCV001072257	SCV001237604	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro