ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.3249G>C (p.Glu1083Asp)

gnomAD frequency: 0.00005  dbSNP: rs147045425
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen RCV000114609 SCV003915579 benign Familial cancer of breast 2023-04-05 reviewed by expert panel curation The c.3249G>C (p.Glu1083Asp) variant in PALB2 is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 1083 (p.Glu1083Asp). This variant has a gnomAD v2.1.1 filtering allele frequency of 0.001331 in the Latino/Admixed American population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. This variant is functional in multiple protein assays; however, due to a lack of positive missense controls with known clinical impact, these assays do not meet the requirements for use by the HBOP VCEP (PMID: 31636395). PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BA1, BP1)
GeneDx RCV000656939 SCV000150011 likely benign not provided 2021-04-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23770606, 26580448, 28779002, 21285249, 26315354, 26689913, 28678401, 30171174, 31636395)
Ambry Genetics RCV000116102 SCV000184769 likely benign Hereditary cancer-predisposing syndrome 2020-03-24 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000114609 SCV000252865 benign Familial cancer of breast 2024-01-24 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 RCV000656939 SCV000601777 likely benign not provided 2022-09-23 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000116102 SCV000686019 likely benign Hereditary cancer-predisposing syndrome 2020-01-07 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212823 SCV002547575 likely benign not specified 2022-05-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000656939 SCV003799324 likely benign not provided 2022-09-15 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000114609 SCV004019631 benign Familial cancer of breast 2023-03-31 criteria provided, single submitter clinical testing This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
PreventionGenetics, part of Exact Sciences RCV004529925 SCV004738983 likely benign PALB2-related disorder 2023-03-16 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000116102 SCV005045380 likely benign Hereditary cancer-predisposing syndrome 2024-04-22 criteria provided, single submitter clinical testing
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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