Submissions for variant NM_007294.4(BRCA1):c.1255G>C (p.Val419Leu)

dbSNP: rs876658873

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220648	SCV000274676	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-31	criteria provided, single submitter	clinical testing	The p.V419L variant (also known as c.1255G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 1255. The valine at codon 419 is replaced by leucine, an amino acid with highly similar properties. This alteration was identified in an individual with a personal and family history of breast cancer (Carney ME et al. Hawaii Med J 2010 Nov; 69(11):268-71). 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.
Invitae	RCV000467786	SCV000549387	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-13	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 419 of the BRCA1 protein (p.Val419Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 21218378). ClinVar contains an entry for this variant (Variation ID: 230967). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587670	SCV000698841	uncertain significance	not provided	2016-06-10	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.1255G>C (p.Val419Leu) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome; functional studies had not been published at the time of variant classification. This variant was absent in 121208 control chromosomes, but was reported in one breast cancer patient diagnosed at 72 years old without evidence of causality (i.e. co-segregation data). Additionally, one clinical lab classified the variant as a VUS. Taken together, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587670	SCV001133479	uncertain significance	not provided	2021-05-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220648	SCV001360193	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-29	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 419 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006522), and it has also been reported in an individual affected with breast or ovarian cancer (PMID: 28364669). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000220648	SCV003846070	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000502439	SCV000591321	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Leu419Val variant has been reported in the literature in 1 of 546 proband chromosomes in an individual with breast cancer with late onset (Carney_2010). However, population controls were not included in this study, and so the prevalence of this variant in the general population is not known. The p.Leu419 residue is not well conserved in mammals and computational analyses (SIFT, Polyphen, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. But this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.