ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9086C>T (p.Ala3029Val) (rs80359162)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129861 SCV000184678 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077459 SCV000147532 uncertain significance Breast-ovarian cancer, familial 2 2001-10-29 no assertion criteria provided 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.
Integrated Genetics/Laboratory Corporation of America RCV000479673 SCV000916966 uncertain significance not specified 2017-10-16 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9086C>T (p.Ala3029Val) variant involves the alteration of a conserved nucleotide and is located in OB2 domain of the protein (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 8/244478 control chromosomes (gnomAD) at a frequency of 0.0000327, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). It has been reported in literature without strong evidence for or against pathogenicity (Karchin_2008, de Smith_2016). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is classified as Variant of Unknown Significance.
Invitae RCV000045708 SCV000073721 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-01 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 not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 52744). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the BRCA2 gene (PMID: 19043619), all suggest that this missense change is likely to be tolerated. The valine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. However, these predictions have not been confirmed by published functional 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.
Mendelics RCV000045708 SCV000838891 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479673 SCV000296524 uncertain significance not specified 2017-04-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077459 SCV000109257 uncertain significance Breast-ovarian cancer, familial 2 2007-11-30 no assertion criteria provided clinical testing

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