Submissions for variant NM_000059.4(BRCA2):c.7559G>C (p.Arg2520Pro)

dbSNP: rs80358982

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122929	SCV000166187	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 2520 of the BRCA2 protein (p.Arg2520Pro). This variant is present in population databases (rs80358982, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer, kidney cancer, and/or kidney renal clear cell carcinoma (PMID: 29484706, 29625052, 36451132). ClinVar contains an entry for this variant (Variation ID: 135815). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 35736817). 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.
Ambry Genetics	RCV000214969	SCV000277162	likely benign	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000479153	SCV000566463	uncertain significance	not specified	2017-04-13	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7559G>C at the cDNA level, p.Arg2520Pro (R2520P) at the protein level, and results in the change of an Arginine to a Proline (CGA>CCA). Using alternate nomenclature, this variant would be defined as BRCA2 7787G>C. This variant has been observed in at least one individual with kidney cancer (Lu 2015). BRCA2 Arg2520Pro 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 Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Arg2520Pro occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located within the DNA binding domain and within a region that interacts with FANCD2 (Yang 2002, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Arg2520Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000214969	SCV000683888	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 2520 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not impact homology-directed DNA repair activity (PMID: 35736817). This variant has been reported in one individual affected with breast cancer and one individual affected with kidney cancer (PMID: 26689913, 29484706). This variant has been identified in 1/245866 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985588	SCV001133907	uncertain significance	not provided	2019-04-19	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV000479153	SCV001251296	benign	not specified	2019-09-01	no assertion criteria provided	research