Submissions for variant NM_000059.4(BRCA2):c.6652G>C (p.Asp2218His)

dbSNP: rs730881547

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160117	SCV000210398	uncertain significance	not provided	2014-04-18	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6652G>C at the cDNA level, p.Asp2218His (D2218H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant, also known as BRCA2 c.6880G>C using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asp2218His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp2218His occurs at a position that is moderately conserved across species and is not located in a known functional domain. 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 Asp2218His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000509725	SCV000607926	uncertain significance	Hereditary cancer-predisposing syndrome	2016-08-06	criteria provided, single submitter	clinical testing	The p.D2218H variant (also known as c.6652G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 6652. The aspartic acid at codon 2218 is replaced by histidine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 300000 alleles tested) in our clinical cohort. This amino acid position is not well 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	RCV001210152	SCV001381623	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-09-13	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 2218 of the BRCA2 protein (p.Asp2218His). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 182230). 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. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509725	SCV003847338	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).