Submissions for variant NM_007294.4(BRCA1):c.1786C>G (p.Leu596Val)

dbSNP: rs80357371

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001013178	SCV001173728	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-22	criteria provided, single submitter	clinical testing	The p.L596V variant (also known as c.1786C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 1786. The leucine at codon 596 is replaced by valine, 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.
Color Diagnostics, LLC DBA Color Health	RCV001013178	SCV001354710	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 596 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. A multifactorial analysis reported likelihood ratios for pathogenicity based on on tumor pathology, segregation and family history of 0.4, 0.9986 and 1.2796, respectively (PMID: 31131967). This variant has been identified in 2/251094 chromosomes 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001368144	SCV001564526	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-01	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 596 of the BRCA1 protein (p.Leu596Val). This variant is present in population databases (rs80357371, gnomAD 0.002%). 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: 54347). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265583	SCV002548449	uncertain significance	not specified	2022-05-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1786C>G (p.Leu596Val) 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 allele was found at a frequency of 8e-06 in 251094 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1786C>G has been reported in the literature in individual(s) affected with Hereditary Breast And Ovarian Cancer Syndrome (Judkins_2005). These reports 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. The variant was analyzed via multifactorial analysis which concluded there was insufficient data to assign an IARC classification (Parsons_2019). Three ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001013178	SCV003849735	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).
All of Us Research Program, National Institutes of Health	RCV000111683	SCV004818283	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 596 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a multifactorial analysis that provided likelihood ratios on tumor pathology, segregation and family history of 0.4, 0.9986 and 1.2796, respectively (PMID: 31131967). This variant has been identified in 2/251094 chromosomes 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111683	SCV000144183	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing