ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.3249G>C (p.Glu1083Asp) (rs147045425)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656939 SCV000150011 uncertain significance not provided 2018-08-06 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.3249G>C at the cDNA level, p.Glu1083Asp (E1083D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant was observed in individuals with breast cancer, renal cancer, and leukemia, but has also been identified in a healthy control (Casadei 2011, Lu 2015, Ramus 2015, Zhang 2015, Decker 2017). PALB2 Glu1083Asp was observed at an allele frequency of 0.17% (58/34,420) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located in the 5th WD repeat, as well as in a region of interaction with RAD51, BRCA2, and POLH, and within a region required for POLH DNA synthesis stimulation (Oliver 2009, Buisson 2010, Buisson 2014, Uniprot). 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 PALB2 Glu1083Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000116102 SCV000184769 likely benign Hereditary cancer-predisposing syndrome 2020-03-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000114609 SCV000252865 benign Familial cancer of breast 2020-12-06 criteria provided, single submitter clinical testing
Counsyl RCV000114609 SCV000488614 uncertain significance Familial cancer of breast 2016-05-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212823 SCV000601777 uncertain significance not specified 2017-06-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000116102 SCV000686019 likely benign Hereditary cancer-predisposing syndrome 2020-01-07 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761171 SCV000891087 uncertain significance Anaplastic ependymoma 2017-04-03 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV000114609 SCV001424776 uncertain significance Familial cancer of breast 2019-03-22 criteria provided, single submitter clinical testing The c.3249G>C variant has been reported in individuals with cancer, including breast cancer, renal cancer and leukemia, as well a healthy control (Decker 2017, Ramus 2015, Lu 2015, Zhang 2015, Casadei 2011). The c.3249G>C variant has an overall allele frequency of 0.0002 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/), and is more common in individuals of Latino ancestry (Lek 2016). Thus, it is unknown at this time whether this variant increases cancer risk.
Leiden Open Variation Database RCV000114609 SCV001193375 uncertain significance Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.

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