Submissions for variant NM_000059.4(BRCA2):c.8774A>G (p.Gln2925Arg)

dbSNP: rs80359135

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481564	SCV000566736	uncertain significance	not provided	2021-11-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (Lek 2016); Also known as 9002A>G; This variant is associated with the following publications: (PMID: 19043619, 29394989, 29409476, 30675319, 29884841, 12228710)
Ambry Genetics	RCV000510072	SCV000607811	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-26	criteria provided, single submitter	clinical testing	The p.Q2925R variant (also known as c.8774A>G), located in coding exon 21 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8774. The glutamine at codon 2925 is replaced by arginine, an amino acid with highly similar properties. A homology-directed DNA repair (HDR) assay demonstrated p.Q2925R to have intermediate functionality, with a probability of pathogenicity of 0.091 and a probability of neutrality of 0.909 (Guidugli L et al. Am. J. Hum. Genet. 2018 02;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80). 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.
Color Diagnostics, LLC DBA Color Health	RCV000510072	SCV000906955	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 2925 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). A functional study has shown this variant has intermediate impact on homology-directed DNA repair activity (PMID: 29394989). This variant has been reported in two individuals affected with breast cancer (PMID: 29409476). This variant has been identified in 1/250670 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001294524	SCV001483404	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 2925 of the BRCA2 protein (p.Gln2925Arg). This variant is present in population databases (rs80359135, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 29409476). ClinVar contains an entry for this variant (Variation ID: 52677). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 29394989). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481564	SCV004220627	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/250670 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 29409476 (2018)). In addition, experimental studies report this variant has an intermediate effect on BRCA2 homology-directed repair function (PMID: 29394989 (2018), 29884841 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003478984	SCV004222892	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8774A>G (p.Gln2925Arg) results in a conservative amino acid change located in the BRCA2, OB2 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250670 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8774A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Abdel-Razeq_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In addition, an HDR assay has reported the variant to have an intermediate impact on HDR function (Guidugli_2018) while computational assays have reported the variant as likely t be neutral (Hart_2019). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000113999	SCV004846069	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-30	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113999	SCV000147460	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing