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

dbSNP: rs80357415

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047765	SCV000075778	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-16	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 54505). This missense change has been observed in individual(s) with breast cancer (PMID: 17221156, 34178674). This variant is not present in population databases (gnomAD no frequency). 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).
Ambry Genetics	RCV000220800	SCV000277172	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-12	criteria provided, single submitter	clinical testing	The p.V740L variant (also known as c.2218G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 2218. The valine at codon 740 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in two breast or ovarian cancer patients undergoing genetic testing based on suspicion for HBOC (Russo A et al. Breast Cancer Res Treat, 2007 Nov;105:267-76; Fanale D et al. Front Oncol, 2021 Jun;11:682445). This amino acid position is not well conserved in available 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.
Color Diagnostics, LLC DBA Color Health	RCV000220800	SCV000688374	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 740 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with breast cancer (PMID: 17221156, 34178674). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811336	SCV001473446	uncertain significance	not provided	2023-09-08	criteria provided, single submitter	clinical testing	The BRCA1 c.2218G>C; p.Val740Leu variant (rs80357415) is reported in the literature in at least two individuals affected with breast cancer (Russo 2007, Fanale 2021). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.338). Due to limited information, the clinical significance of the p.Val740Leu variant is uncertain at this time. References: Fanale D et al. Prevalence and Spectrum of Germline BRCA1 and BRCA2 Variants of Uncertain Significance in Breast/Ovarian Cancer: Mysterious Signals From the Genome. Front Oncol. 2021 Jun 11;11:682445. PMID: 34178674 Russo A et al. BRCA1 genetic testing in 106 breast and ovarian cancer families from Southern Italy (Sicily): a mutation analyses. Breast Cancer Res Treat. 2007 Nov;105(3):267-76. PMID: 17221156
University of Washington Department of Laboratory Medicine, University of Washington	RCV000220800	SCV003847846	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	RCV001811336	SCV003930941	uncertain significance	not provided	2023-06-07	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer (Russo et al., 2007; Fanale et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 2337G>C; This variant is associated with the following publications: (PMID: 25011685, 34178674, 15343273, 31853058, 29884841, 17221156)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001811336	SCV004222591	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 34178674 (2021), 17221156 (2007)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111798	SCV000144343	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing