Submissions for variant NM_000059.4(BRCA2):c.902A>G (p.Asp301Gly)

gnomAD frequency: 0.00001  dbSNP: rs730881508

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160032	SCV000210259	uncertain significance	not provided	2014-01-07	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.902A>G at the cDNA level and p.Asp301Gly (D301G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This variant is a non-conservative amino acid substitution in which a negative polar residue is replaced with a neutral non-polar one, altering a position that is only moderately conserved throughout evolution, and is not in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on currently available information, we consider this to be a variant of uncertain significance.
Ambry Genetics	RCV000166054	SCV000216815	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-16	criteria provided, single submitter	clinical testing	The p.D301G variant (also known as c.902A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 902. The aspartic acid at codon 301 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545109	SCV000635711	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 301 of the BRCA2 protein (p.Asp301Gly). This variant is present in population databases (rs730881508, gnomAD 0.002%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 34026625). ClinVar contains an entry for this variant (Variation ID: 182182). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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	RCV000166054	SCV000689170	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-25	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 301 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 a BRCA2-associated cancer (PMID: 34026625). This variant has been identified in 2/239400 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265633	SCV002548437	uncertain significance	not specified	2022-05-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.902A>G (p.Asp301Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-06 in 239400 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.902A>G has been reported in the literature in at least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome. This report does 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. Three 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166054	SCV003848125	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).