ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.2379C>T (p.Gly793=) (rs377626805)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212811 SCV000149993 uncertain significance not provided 2018-07-23 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.2379C>T at the DNA level. It is silent at the coding level, preserving a Glycine at codon 793. In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. This variant has been observed in several individuals with a personal and/or family history of breast cancer (Catucci 2014, Damiola 2015, Thompson 2015, Decker 2017). PALB2 c.2379C>T was observed at an allele frequency of 0.01% (15/126,706) in individuals of European ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether PALB2 c.2379C>T is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000116084 SCV000213044 likely benign Hereditary cancer-predisposing syndrome 2017-05-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,RNA Studies
Invitae RCV000212811 SCV000255086 likely benign not provided 2019-03-03 criteria provided, single submitter clinical testing
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000200135 SCV000268050 likely benign Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Illumina Clinical Services Laboratory,Illumina RCV000292657 SCV000396096 uncertain significance Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000116084 SCV000396097 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Color RCV000116084 SCV000685946 likely benign Hereditary cancer-predisposing syndrome 2018-05-16 criteria provided, single submitter clinical testing
Mendelics RCV000116084 SCV000839021 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780574 SCV000917963 uncertain significance not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: PALB2 c.2379C>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools via ALAMUT predict a significant impact on normal splicing: Four predict the variant creates a cryptic 5 donor site in exon 5. Another in-silico tool for assessing the pathogenicity of synonymous variants, namely TraP (Transcript-inferred Pathogenicity, Gelfman_2017) predicts this variant to be possibly pathogenic. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.4e-05 in 256744 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer (7.4e-05 vs 0.00016), allowing no conclusion about variant significance. The variant, c.2379C>T, has been reported in the literature in individuals affected with breast, ovarian and pancreatic cancers (Catucci_2014, Damiola_2015, Thompson_2015, Borecka_2016, Decker_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. In addition, this variant was found in four healthy older women in FLOSSIES database, suggesting that the variant could be benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Uncertain Significance x3, Likely Benignx4). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.