ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9365C>T (p.Ala3122Val) (rs571971903)

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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 RCV000570908 SCV000665036 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000570908 SCV000689192 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-21 criteria provided, single submitter clinical testing
GeneDx RCV000484126 SCV000570518 uncertain significance not provided 2017-01-26 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9365C>T at the cDNA level, p.Ala3122Val (A3122V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). Using alternate nomenclature, this variant would be defined as BRCA2 9593C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala3122Val was not observed at a significant allele frequency in 1000 Genomes and was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ala3122Val occurs at a position that is conserved across species and is located in the DNA binding domain (Yang 2002). 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 Ala3122Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205376 SCV000261341 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-10-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 3122 of the BRCA2 protein (p.Ala3122Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs571971903, ExAC 0.01%) but has not been reported in the literature. 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: "Probably Damaging"; Align-GVGD: "Class C0"). Furthermore, algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare missense change with uncertain impact on protein function and splicing. It has been classified as a Variant of Uncertain Significance.

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