Submissions for variant NM_000059.4(BRCA2):c.6818G>A (p.Arg2273Lys)

dbSNP: rs587782174

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130779	SCV000185672	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-07	criteria provided, single submitter	clinical testing	The p.R2273K variant (also known as c.6818G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6818. The arginine at codon 2273 is replaced by lysine, an amino acid with highly similar properties. This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is well 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.
Fulgent Genetics, Fulgent Genetics	RCV000765132	SCV000896358	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130779	SCV001355525	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 2273 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 an individual affected with endometrial cancer with a family history of breast and/or ovarian cancer (PMID: 32885271). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857455	SCV002211264	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 2273 of the BRCA2 protein (p.Arg2273Lys). 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: 142005). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130779	SCV003847475	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).
GeneDx	RCV000501677	SCV003919569	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with cutaneous melanoma and other cancers (Pritchard et al., 2018); Also known as 7046G>A; This variant is associated with the following publications: (PMID: 29641532, 32377563, 31911673)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000501677	SCV000592076	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Arg2273Lys variant was identified in the literature however the frequency of this variant in an affected population was not provided (Neveling_2017_27974384). The variant was also identified in dbSNP (ID: rs587782174) as “With Uncertain significance allele,” ClinVar (as uncertain significance by Ambry Genetics, and previously reported by Mount Sinai), Clinvitae (2x as uncertain significance), GeneInsight-COGR (as uncertain significance as previously reported by Mount Sinai), and Cosmic (1x in urinary tract tumour) databases. The variant was not identified in MutDB, LOVD 3.0, UMD-LSDB, BIC Database, or ARUP Laboratories databases. Our laboratory has identified this variant once before in a 41 year old female who had a strong family history of breast and ovarian cancer but did not have cancer herself. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Arg2273 residue is not conserved in mammals and the variant amino acid Lysine (Lys) is present in fishes, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.