ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9838C>T (p.Pro3280Ser) (rs55835607)

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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 RCV000509955 SCV000607793 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA2) RCV000077476 SCV000145718 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000509955 SCV000684093 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
GeneDx RCV000487013 SCV000566872 uncertain significance not provided 2018-12-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9838C>T at the cDNA level, p.Pro3280Ser (P3280S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). Using alternate nomenclature, this variant would be defined as BRCA2 10066C>T. This variant showed complementation and homology directed repair capacity similar to wild type and did not significantly impact sensitivity to DNA damaging agents in in vitro functional studies (Mesman 2018). BRCA2 Pro3280Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Pro3280Ser is not located in a known functional domain. 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 Pro3280Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000045903 SCV000073916 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 3280 of the BRCA2 protein (p.Pro3280Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs55835607, ExAC 0.01%). This variant has been observed in individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in one of those individuals, a pathogenic allele was also identified in BRCA1, which suggests that this c.9838C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 52905). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000077476 SCV000109274 likely benign Breast-ovarian cancer, familial 2 2010-09-09 no assertion criteria provided clinical testing

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