Submissions for variant NM_000059.4(BRCA2):c.8393C>G (p.Pro2798Arg)

dbSNP: rs276174906

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000218832	SCV000279407	uncertain significance	not provided	2016-02-24	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8393C>G at the cDNA level, p.Pro2798Arg (P2798R) at the protein level, and results in the change of a Proline to an Arginine (CCT>CGT). Using alternate nomenclature, this variant would be defined as BRCA2 8621C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Pro2798Arg 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 Proline and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Pro2798Arg occurs at a position that is conserved across species and is located in the DSS1 contacting residue and SHFM1 binding domain (Marston 1999, Yang 2002). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Pro2798Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375565	SCV001572450	uncertain significance	not specified	2021-04-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8393C>G (p.Pro2798Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8393C>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer (example, Incorvaia_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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003530016	SCV004250968	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-09	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 234511). This missense change has been observed in individual(s) with breast cancer (PMID: 34178674). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2798 of the BRCA2 protein (p.Pro2798Arg).
All of Us Research Program, National Institutes of Health	RCV003998621	SCV004835378	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 2798 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer (PMID: 32380732, 34178674). 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.
Ambry Genetics	RCV004020703	SCV005030703	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The p.P2798R variant (also known as c.8393C>G), located in coding exon 18 of the BRCA2 gene, results from a C to G substitution at nucleotide position 8393. The proline at codon 2798 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly 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.
Baylor Genetics	RCV004567679	SCV005058354	uncertain significance	Familial cancer of breast	2024-03-21	criteria provided, single submitter	clinical testing