Submissions for variant NM_007294.4(BRCA1):c.2218G>T (p.Val740Leu)

dbSNP: rs80357415

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164916	SCV000215604	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	The p.V740L variant (also known as c.2218G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2218. The valine at codon 740 is replaced by leucine, an amino acid with highly similar properties. A similar alteration, c.2218G>C, leading to the same amino acid change (p.V740L) has been reported in 1/650 Sicilian breast and/or ovarian cancer patients (Russo A et al. Breast Cancer Res. Treat., 2007 Nov;105:267-76). This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000539119	SCV000635836	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 740 of the BRCA1 protein (p.Val740Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 17221156). ClinVar contains an entry for this variant (Variation ID: 185481). 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.
Counsyl	RCV000662700	SCV000785442	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-08-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328454	SCV001519595	uncertain significance	not specified	2021-03-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2218G>T (p.Val740Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250964 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2218G>T has been reported in the literature in at-least one individual affected with Hereditary Breast Cancer (example, Russo_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164916	SCV003847845	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).