ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9443C>T (p.Ala3148Val) (rs587781514)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129493 SCV000184265 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
GeneDx RCV000160170 SCV000210507 uncertain significance not provided 2014-06-09 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9443C>T at the cDNA level, p.Ala3148Val (A3148V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). Of note, this variant is also known as BRCA2 c.9671C>T by alternate nomenclature. 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, suggesting it is not a common benign variant in these populations. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ala3148Val occurs at a position that is well conserved across species and is not located in a known functional domain. In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider BRCA2 Ala3148Val to be a variant of uncertain significance.Based on the reported results of this patientÂ’s relativeÂ’s testing, the BRCA2 pathogenic variant and BRCA2 variant of uncertain significance are on the same chromosome (in cis).
Color RCV000129493 SCV000684065 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing
Invitae RCV000695537 SCV000824044 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 3148 of the BRCA2 protein (p.Ala3148Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. 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: 141127). Algorithms developed to predict the effect of missense changes on protein structure and function 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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