ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6683T>C (p.Val2228Ala) (rs80358894)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166253 SCV000217033 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Breast Cancer Information Core (BIC) (BRCA2) RCV000113629 SCV000146911 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Counsyl RCV000113629 SCV000488644 uncertain significance Breast-ovarian cancer, familial 2 2016-05-12 criteria provided, single submitter clinical testing
GeneDx RCV000236365 SCV000293629 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6683T>C at the cDNA level, p.Val2228Ala (V2228A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). Using alternate nomenclature, this variant would be defined as BRCA2 6911T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Val2228Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val2228Ala is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Val2228Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000045017 SCV000073030 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 2228 of the BRCA2 protein (p.Val2228Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs80358894, ExAC 0.005%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 52156). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236365 SCV000887884 uncertain significance not provided 2017-11-09 criteria provided, single submitter clinical testing

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