ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5672C>T (p.Ala1891Val) (rs397507360)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000758912 SCV000210362 uncertain significance not provided 2014-05-29 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5672C>T at the cDNA level, p.Ala1891Val (A1891V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although the variant creates a new cryptic donor site, the probability of it being used is significantly lower than the natural donor site; thus, the cryptic site is unlikely to have a deleterious effect on the protein. BRCA2 Ala1891Val 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 Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ala1891Val occurs at a position that is highly variable across species and is not located in a known functional domain. In addition, in silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Ala1891Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000460706 SCV000549738 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1891 of the BRCA2 protein (p.Ala1891Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs397507360, ExAC 0.003%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 37987). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160094 SCV000600655 uncertain significance not specified 2017-07-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562290 SCV000665959 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758912 SCV000887855 uncertain significance not provided 2018-08-03 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031568 SCV000054173 uncertain significance Breast-ovarian cancer, familial 2 2009-12-14 no assertion criteria provided clinical testing

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