ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7631G>A (p.Gly2544Asp) (rs397507926)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214936 SCV000274872 uncertain significance Hereditary cancer-predisposing syndrome 2015-03-30 criteria provided, single submitter clinical testing
GeneDx RCV000483279 SCV000566447 uncertain significance not provided 2015-04-29 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7631G>A at the cDNA level, p.Gly2544Asp (G2544D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGC>GAC). This variant, also published as BRCA2 7859G>A using alternate nomenclature, has been reported in at least one woman of Asian descent with a personal and family history of breast cancer (Ang 2007). BRCA2 Gly2544Asp 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 Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gly2544Asp occurs at a position that is conserved across species and is located in the DNA binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Gly2544Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000045271 SCV000073284 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 2544 of the BRCA2 protein (p.Gly2544Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (rs397507926, ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 18006916, 26221963, 29263802 28664506). ClinVar contains an entry for this variant (Variation ID: 52373). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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.

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