Submissions for variant NM_000059.4(BRCA2):c.9171C>G (p.Phe3057Leu)

dbSNP: rs747615055

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166134	SCV000216906	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-04	criteria provided, single submitter	clinical testing	The p.F3057L variant (also known as c.9171C>G), located in coding exon 23 of the BRCA2 gene, results from a C to G substitution at nucleotide position 9171. The phenylalanine at codon 3057 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687351	SCV000814914	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-05	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 3057 of the BRCA2 protein (p.Phe3057Leu). This variant is present in population databases (rs747615055, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 32438681). ClinVar contains an entry for this variant (Variation ID: 186525). 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 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.
Color Diagnostics, LLC DBA Color Health	RCV000166134	SCV001359810	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 3057 of the BRCA2 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 an individual affected with breast and/or ovarian cancer (PMID: 32438681). This variant has been identified in 1/251288 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.
GeneDx	RCV002472957	SCV002770185	uncertain significance	not provided	2022-12-22	criteria provided, single submitter	clinical testing	Observed in individuals with breast and/or ovarian cancer (Santonocito et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9399C>G; This variant is associated with the following publications: (PMID: 32377563, 32438681, 12228710, 29884841)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002472957	SCV004220642	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with breast and/or ovarian cancer (PMID: 32438681 (2020)). The frequency of this variant in the general population, 0.000004 (1/251288 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.
All of Us Research Program, National Institutes of Health	RCV004804758	SCV004846132	uncertain significance	BRCA2-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 3057 of the BRCA2 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 an individual affected with breast and/or ovarian cancer (PMID: 32438681). This variant has been identified in 1/251288 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.