Submissions for variant NM_000059.4(BRCA2):c.6700T>C (p.Phe2234Leu)

dbSNP: rs769956199

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000772767	SCV000906147	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985571	SCV001133873	uncertain significance	not provided	2023-02-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251294 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a family with breast and ovarian cancer (PMID: 18060494 (2008)). 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.
Ambry Genetics	RCV000772767	SCV001187761	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The p.F2234L variant (also known as c.6700T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 6700. The phenylalanine at codon 2234 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in one Spanish hereditary breast cancer family (Esteban Cardeñosa E et al. Breast Cancer Res. Treat., 2008 Nov;112:69-73). This amino acid position is highly conserved in available vertebrate species. 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.
GeneDx	RCV000985571	SCV002005059	uncertain significance	not provided	2019-10-29	criteria provided, single submitter	clinical testing	Observed in individuals with breast and/or ovarian cancer (Esteban Cardenosa 2008); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 6928T>C; This variant is associated with the following publications: (PMID: 18060494)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002534033	SCV003025873	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-07	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 2234 of the BRCA2 protein (p.Phe2234Leu). This variant is present in population databases (rs769956199, gnomAD 0.003%). This missense change has been observed in individual(s) with personal and/or family history of breast and ovarian cancer (PMID: 18060494). This variant is also known as c.6928T>C. ClinVar contains an entry for this variant (Variation ID: 628311). 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	RCV000772767	SCV003847380	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).
All of Us Research Program, National Institutes of Health	RCV004802423	SCV005424547	uncertain significance	BRCA2-related cancer predisposition	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 2234 of the BRCA2 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 suspected hereditary breast cancer family (PMID: 18060494). This variant has been identified in 1/251294 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.