Submissions for variant NM_000059.4(BRCA2):c.6952C>G (p.Arg2318Gly)

dbSNP: rs80358920

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461532	SCV000549866	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2318 of the BRCA2 protein (p.Arg2318Gly). 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: 409599). 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.
GeneDx	RCV000485650	SCV000572316	uncertain significance	not provided	2016-11-18	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6952C>G at the cDNA level, p.Arg2318Gly (R2318G) at the protein level, and results in the change of an Arginine to a Glycine (CGA>GGA). Using alternate nomenclature, this variant would be defined as BRCA2 7180C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Arg2318Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Arg2318Gly occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Arg2318Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000573163	SCV000666090	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-04	criteria provided, single submitter	clinical testing	The p.R2318G variant (also known as c.6952C>G), located in coding exon 12 of the BRCA2 gene, results from a C to G substitution at nucleotide position 6952. The arginine at codon 2318 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000573163	SCV000910262	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 2318 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001839454	SCV002098401	uncertain significance	Hereditary nonpolyposis colorectal carcinoma	2022-02-21	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 13 of the BRCA2 gene that results in the amino acid substitution of Glycine for Arginine at codon 2318 was detected. The observed variant c.6952C>G (p.Arg2318Gly) is documented as a variant of uncertain significance in hereditary cancer-predisposing syndrome in the ClinVar database (VCV000409599.10). The variant has not been reported in the 1000 genomes and gnomAD database respectively. The in silico predictions of the variant are probably damaging by PolyPhen-2 and damaging by SIFT, MutationTaster2, and LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV002275033	SCV002562748	uncertain significance	Malignant tumor of esophagus	2022-02-21	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 13 of the BRCA2 gene that results in the amino acid substitution of Glycine for Arginine at codon 2318 was detected. The observed variant c.6952C>G (p.Arg2318Gly) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is probably damaging by PolyPhen-2 (HumDiv), damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across primates. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150219	SCV003838830	uncertain significance	Breast and/or ovarian cancer	2021-07-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476090	SCV004211947	uncertain significance	Familial cancer of breast	2023-09-17	criteria provided, single submitter	clinical testing