ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9086C>T (p.Ala3029Val) (rs80359162)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045708 SCV000073721 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 3029 of the BRCA2 protein (p.Ala3029Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs80359162, ExAC 0.02%). This variant has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 31102422). ClinVar contains an entry for this variant (Variation ID: 52744). This variant has been reported not to substantially affect BRCA2 protein function (PMID: 29884841). 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.
Ambry Genetics RCV000129861 SCV000184678 likely benign Hereditary cancer-predisposing syndrome 2019-12-06 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479673 SCV000296524 uncertain significance not specified 2017-04-01 criteria provided, single submitter clinical testing
Counsyl RCV000077459 SCV000488156 uncertain significance Breast-ovarian cancer, familial 2 2016-02-19 criteria provided, single submitter clinical testing
GeneDx RCV000657008 SCV000566257 uncertain significance not provided 2018-11-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9086C>T at the cDNA level, p.Ala3029Val (A3029V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). Using alternate nomenclature, this variant would be defined as BRCA2 9314C>T. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Ala3029Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ala3029Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Mendelics RCV000045708 SCV000838891 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000479673 SCV000916966 uncertain significance not specified 2019-09-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9086C>T (p.Ala3029Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249594 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9086C>T has been reported in the literature without strong evidence for or against pathogenicity (Karchin_2008, de Smith_2016). In a cell-based homology directed DNA repair activity assay, this variant was found to have neutral effect (Hart_2019). Six other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS possibly benign.
Mendelics RCV000077459 SCV001139246 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129861 SCV001353223 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-05 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 3029 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related cancer in the literature. This variant has been identified in 8/249594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000077459 SCV000109257 uncertain significance Breast-ovarian cancer, familial 2 2007-11-30 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077459 SCV000147532 uncertain significance Breast-ovarian cancer, familial 2 2001-10-29 no assertion criteria provided clinical testing

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