ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9632C>A (p.Thr3211Lys) (rs730881583)

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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 RCV000163095 SCV000213602 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000163095 SCV000903228 likely benign Hereditary cancer-predisposing syndrome 2015-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000160193 SCV000210540 uncertain significance not provided 2018-11-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9632C>A at the cDNA level, p.Thr3211Lys (T3211K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 9860C>A. This variant has been observed in at least one individual with a history of breast cancer (Spearman 2008). BRCA2 Thr3211Lys was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. While protein-based in silico analysis supports that this variant does not alter protein structure/function, splicing models predict the creation of a novel splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 Thr3211Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000472534 SCV000549709 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 3211 of the BRCA2 protein (p.Thr3211Lys). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182275). 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. Algorithms developed to predict the effect of sequence 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 variant is a rare missense change that is not predicted to affect protein function, however it is predicted to alter splicing.  There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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