Submissions for variant NM_000059.4(BRCA2):c.6875A>G (p.Glu2292Gly)

gnomAD frequency: 0.00001  dbSNP: rs397507378

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131009	SCV000185935	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-12	criteria provided, single submitter	clinical testing	The p.E2292G variant (also known as c.6875A>G), located in coding exon 11 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6875. The glutamic acid at codon 2292 is replaced by glycine, an amino acid with similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE, 2014 Apr;9:e94554). This alteration was also detected in 1/581 German breast and/or ovarian cancer patients who were tested with a 14-gene panel (Kraus C et al. Int. J. Cancer, 2017 Jan;140:95-102). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460823	SCV000549571	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2292 of the BRCA2 protein (p.Glu2292Gly). This variant is present in population databases (rs397507378, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 27616075, 32438681). ClinVar contains an entry for this variant (Variation ID: 38071). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Color Diagnostics, LLC DBA Color Health	RCV000131009	SCV000683824	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 2292 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with breast or ovarian cancer (PMID: 27616075, 32438681) but also in two unaffected individuals (PMID: 24728327, 33471991; Leiden Open Variation Database DB-ID BRCA2_001815). This variant has been identified in 4/280182 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.
Counsyl	RCV000031653	SCV000785503	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-08-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755861	SCV000883486	uncertain significance	not provided	2017-07-12	criteria provided, single submitter	clinical testing	The BRCA2 c.6875A>G;p.Glu2292Gly variant has been published in at least one individual with breast cancer (Kraus 2017). The variant is listed in the ClinVar database (Variation ID: 38071) and in the dbSNP variant database (rs397507378) with an allele frequency of 0.001453 percent (4/275354 alleles) in the Genome Aggregation Database. The amino acid at this position is highly conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is damaging. Considering available information, there is insufficient evidence to classify this variant with certainty. References: Kraus C et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer. 2017 Jan 1;140(1):95-102.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120350	SCV000917048	uncertain significance	not specified	2018-11-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6875A>G (p.Glu2292Gly) 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 allele was found at a frequency of 1.5e-05 in 275354 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6875A>G has been reported in the literature in an individual affected with triple negative breast cancer (Kraus_2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000755861	SCV001133878	uncertain significance	not provided	2020-08-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000755861	SCV001825526	uncertain significance	not provided	2024-12-16	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7103A>G; This variant is associated with the following publications: (PMID: 24728327, 32438681, 27616075)
Sema4, Sema4	RCV000131009	SCV002536276	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-27	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004803063	SCV004844324	uncertain significance	BRCA2-related cancer predisposition	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 2292 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with triple-negative breast cancer in the literature (PMID: 27616075) but also in an unaffected individual (PMID: 24728327). This variant has been identified in 4/280182 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.
Baylor Genetics	RCV004566774	SCV005059156	uncertain significance	Familial cancer of breast	2023-12-11	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031653	SCV000054260	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2013-05-29	no assertion criteria provided	clinical testing
ITMI	RCV000120350	SCV000084502	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354025	SCV000592081	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Glu2292Gly variant was not identified in the literature nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, GeneInsight VariantWire database, the BIC database and UMD. The variant was identified in dbSNP (ID: rs397507378) “With uncertain significance allele”; the ClinVar database (classified as a “uncertain significance” variant by the Sharing Clinical Reports Project (derived from Myriad reports) and Ambry Genetics) and in 1 of 64634 European individuals from the Exome Aggregation Consortium (ExAC) database. The p.Glu2292 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Glu2292 variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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 unknown significance.