Submissions for variant NM_000059.4(BRCA2):c.6734T>A (p.Leu2245Gln)

gnomAD frequency: 0.00001  dbSNP: rs772795886

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000504316	SCV000593752	uncertain significance	not specified	2016-08-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509998	SCV000608065	benign	Hereditary cancer-predisposing syndrome	2024-02-21	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000798113	SCV000937712	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 2245 of the BRCA2 protein (p.Leu2245Gln). This variant is present in population databases (rs772795886, gnomAD 0.002%). 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: 434533). 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. 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	RCV000509998	SCV001355523	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with glutamine at codon 2245 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 been reported in a breast cancer case-control meta-analysis in 3/60463 cases and 3/53458 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008497). This variant has been identified in 2/282744 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	RCV001591137	SCV001827176	uncertain significance	not provided	2019-04-12	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV000509998	SCV002536261	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000504316	SCV002761176	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509998	SCV003847408	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001591137	SCV004220518	uncertain significance	not provided	2023-05-02	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000071 (2/282744 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large case-control study, the variant has been reported in individuals with breast cancer as well as in unaffected controls (PMID: 33471991 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. 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	RCV004003524	SCV004844307	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with glutamine at codon 2245 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 been reported in a breast cancer case-control meta-analysis in 3/60463 cases and 3/53458 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008497). This variant has been identified in 2/282744 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.