Submissions for variant NM_000059.4(BRCA2):c.5770A>T (p.Ile1924Phe)

gnomAD frequency: 0.00001  dbSNP: rs779020831

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581357	SCV000688947	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with phenylalanine at codon 1924 of the BRCA2 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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001040894	SCV001204485	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1924 of the BRCA2 protein (p.Ile1924Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 491297). 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 BRCA2 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000581357	SCV003849092	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).
Ambry Genetics	RCV000581357	SCV003855494	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-06	criteria provided, single submitter	clinical testing	The p.I1924F variant (also known as c.5770A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 5770. The isoleucine at codon 1924 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478313	SCV004220471	uncertain significance	not provided	2023-11-09	criteria provided, single submitter	clinical testing	The BRCA2 c.5770A>T (p.Ile1924Phe) variant has not been reported in individuals with BRCA2-related conditions in the published literature. However, it has been described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.0000066 (1/152210 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.