ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9589G>C (p.Asp3197His) (rs876660053)

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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 RCV000221515 SCV000277144 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-14 criteria provided, single submitter clinical testing
GeneDx RCV000213469 SCV000279938 uncertain significance not provided 2016-02-25 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9589G>C at the cDNA level, p.Asp3197His (D3197H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAC>CAC). Using alternate nomenclature, this variant would be defined as BRCA2 9817G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asp3197His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting 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 Asp3197His occurs at a position that is not conserved and is not located in a known functional domain (Cole 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Asp3197His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000795570 SCV000935038 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 3197 of the BRCA2 protein (p.Asp3197His). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 232888). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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