Submissions for variant NM_007294.4(BRCA1):c.2893C>T (p.Leu965Phe)

dbSNP: rs1060502344

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001063596	SCV001228450	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-29	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: 857839). This missense change has been observed in individual(s) with breast cancer (PMID: 18284688). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 965 of the BRCA1 protein (p.Leu965Phe).
Color Diagnostics, LLC DBA Color Health	RCV001192250	SCV001360277	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002240501	SCV002511778	uncertain significance	not specified	2022-04-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2893C>T (p.Leu965Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251380 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2893C>T has been reported in the literature as a VUS in at-least one individual from a population based cohort of breast cancer patients diagnosed between 20 and 49 years who underwent BRCA1/2 testing (example, Lee_2008). 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. Two 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. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV001192250	SCV002751337	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	The p.L965F variant (also known as c.2893C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2893. The leucine at codon 965 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was identified in a non-Hispanic white individual from a population-based study of early-onset breast cancer diagnoses (Lee E et al. Breast Cancer Res., 2008 Feb;10:R19). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001192250	SCV003849276	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).