ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.2559C>T (p.Gly853=) (rs180177115)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116088 SCV000187359 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: RNA Studies,Functionally-validated splicing mutation
GeneDx RCV000212813 SCV000149997 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.2559C>T at the DNA level. Although the variant is silent at the coding level, preserving a Glycine at codon 853, it is predicted to cause abnormal splicing by creating a cryptic splice donor site. While Casadei et al. (2011) confirmed in an mRNA based assay that this variant does alter splicing and results in the out-of-frame deletion of 29 base pairs of exon 6, it is not clear to what extent this aberrant transcript is expressed compared to the wildtype transcript. In addition, PALB2 c.2559C>T has been reported in 1/972 women with a personal and family history of breast cancer and was absent in 960 control subjects (Casadei 2011). Based on the currently available information, we consider PALB2 2559C>T to be a variant of uncertain significance.
Invitae RCV000114536 SCV000550690 uncertain significance Familial cancer of breast 2018-11-18 criteria provided, single submitter clinical testing This sequence change affects codon 853 of the PALB2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PALB2 protein. This variant is present in population databases (rs180177115, ExAC 0.003%). This variant has been reported in an individual affected with breast cancer (PMID: 21285249), and an individual affected with pancreatic cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 126660). An experimental study has shown that this variant alters mRNA splicing by creating a new splice site that results in the deletion of 29 nucleotides (PMID: 21285249). This is expected to result in a frameshift and truncated protein. While truncating variants in PALB2 protein are typically deleterious, additional experimental evidence is needed to confirm the effect of this silent variant on splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PALB2 database RCV000114536 SCV000148482 likely pathogenic Familial cancer of breast 2012-07-16 no assertion criteria provided literature only

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