ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.241C>T (p.Pro81Ser) (rs104893829)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115744 SCV000212872 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting benign classification
CSER_CC_NCGL; University of Washington Medical Center RCV000002321 SCV000190677 likely benign Von Hippel-Lindau syndrome 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing for an unrelated indication. No known history of von Hippel-Lindau syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761019 SCV000890934 uncertain significance Wilms Tumor 2016-03-07 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000418681 SCV000505320 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000002321 SCV000264680 uncertain significance Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
GeneDx RCV000656990 SCV000149653 uncertain significance not provided 2018-11-06 criteria provided, single submitter clinical testing This variant is denoted VHL c.241C>T at the cDNA level, p.Pro81Ser (P81S) at the protein level, and results in the change of a Proline to a Serine (CCG>TCG). VHL Pro81Ser was observed at an allele frequency of 0.05% (54/118062) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). VHL Pro81Ser is located in the Beta-domain (Yuen 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. This variant, also known as VHL 454C>T using alternate nomenclature, has been reported in several individuals and families with Von Hippel Lindau-related cancers (Clinical Research Group for VHL in Japan 1995, Glavac 1996, Stolle 1998, Glasker 1999, Hes 2000, Weirich 2002, Erlic 2010, Haitz 2015, Alosi 2017). However, some pieces of evidence reduce the likelihood of pathogenicity, or suggest reduced penetrance. First, this variant was identified in families who also carried a likely pathogenic VHL variant in cis (Weirich 2002, Erlic 2010). In addition, this variant was identified in a family with a large deletion of the entire VHL gene in trans, in which VHL Pro81Ser did not segregate with disease (Erlic 2010). Finally, this variant has been identified in at least three unrelated probands with isolated hemangioblastoma or renal cell carcinoma with no affected family members, including some at older ages who carried the variant (Hes 2000, Haitz 2015, Alosi 2017). Therefore, while this variant was probably not solely responsible for cancer in these families, some authors suggest that VHL Pro81Ser might be a low penetrance allele or a modifier variant. Some functional studies suggest normal activity (Knauth 2009), while others suggest this variant may lead to lack of ubiquitination, reduced DNA damage response, and resistance to ionizing radiation-induced apoptosis (Li 2002, Desimone 2013). Therefore, despite some functional and family segregation data suggesting neutrality, since we cannot rule out a modifying or low penetrance effect, we consider VHL Pro81Ser to be a variant of uncertain significance.
Gharavi Laboratory,Columbia University RCV000656990 SCV000920742 likely benign not provided 2018-09-16 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000002321 SCV000053257 likely benign Von Hippel-Lindau syndrome 2015-10-02 no assertion criteria provided clinical testing
Invitae RCV000225752 SCV000254650 benign Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2017-12-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000213077 SCV000540657 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Several reports describe as LB/non-pathogenic; ExAC: 0.04% (19/53684) European chromosomes
OMIM RCV000002321 SCV000022479 pathogenic Von Hippel-Lindau syndrome 2002-11-01 no assertion criteria provided literature only
PreventionGenetics RCV000656990 SCV000805331 likely benign not provided 2017-10-02 criteria provided, single submitter clinical testing

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