Submissions for variant NM_000059.4(BRCA2):c.2014A>G (p.Arg672Gly)

gnomAD frequency: 0.00001  dbSNP: rs587781647

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129778	SCV000184587	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-12	criteria provided, single submitter	clinical testing	The p.R672G variant (also known as c.2014A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2014. The arginine at codon 672 is replaced by glycine, an amino acid with dissimilar properties. This variant was detected in 1/2351 Italian breast and/or ovarian cancer patients and was classified as likely benign (Santonocito C et al. Cancers (Basel), 2020 May;12:). This alteration has also been detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod. Pathol., 2016 11;29:1381-1389). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000160042	SCV000210281	uncertain significance	not provided	2014-10-01	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.2014A>G at the cDNA level, p.Arg672Gly (R672G) at the protein level, and results in the change of an Arginine to a Glycine (AGA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Arg672Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Arg672Gly occurs at a position that is variable across mammals and is located in the Interaction with NPM1 region (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Arg672Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000456158	SCV000549609	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-24	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 672 of the BRCA2 protein (p.Arg672Gly). This variant is present in population databases (rs587781647, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer, and endometrial cancer (PMID: 27443514, 32438681). ClinVar contains an entry for this variant (Variation ID: 141308). 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	RCV000129778	SCV000903470	likely benign	Hereditary cancer-predisposing syndrome	2016-04-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375553	SCV001572426	uncertain significance	not specified	2021-04-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2014A>G (p.Arg672Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248450 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2014A>G has been reported in the literature in individuals affected with endometrial and/or breast cancer undergoing multigene panel testing (example, Ring_2016, Santonocito_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n=2; likely benign, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129778	SCV003846439	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	RCV000160042	SCV004219529	uncertain significance	not provided	2022-12-12	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000012 (3/248450 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMIDs: 32438681 (2020) and 33471991 (2021)), as well as individuals with endometrial cancer (PMID: 27443514 (2016)). 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.