Submissions for variant NM_007294.4(BRCA1):c.2872T>C (p.Phe958Leu)

dbSNP: rs80356878

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166226	SCV000217005	uncertain significance	Hereditary cancer-predisposing syndrome	2014-10-20	criteria provided, single submitter	clinical testing	The p.F958L variant (also known as c.2872T>C and 2991T>C) is located in coding exon 9 of the BRCA1 gene. This alteration results from a T to C substitution at nucleotide position 2872. The phenylalanine at codon 958 is replaced by leucine, an amino acid with some similar properties. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. 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 p.F958L remains unclear.
Invitae	RCV000637436	SCV000758895	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 958 of the BRCA1 protein (p.Phe958Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with BRCA1-related cancer (PMID: 27062684). ClinVar contains an entry for this variant (Variation ID: 186606). 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.
Illumina Laboratory Services, Illumina	RCV001122178	SCV001280876	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV000166226	SCV001359690	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-06	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166226	SCV003849295	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).