ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.3113+5G>C (rs876659463)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214215 SCV000275968 likely pathogenic Hereditary cancer-predisposing syndrome 2017-09-22 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,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),RNA Studies
Color RCV000214215 SCV000903684 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-19 criteria provided, single submitter clinical testing
GeneDx RCV000255512 SCV000322190 likely pathogenic not provided 2016-06-17 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.3113+5G>C or IVS10+5G>C and consists of a G>C nucleotide substitution at the +5 position of intron 10 of the PALB2 gene. Multiple in silico models predict this variant to destroy the nearby natural donor site and to result in abnormal splicing. Reid et al. (2007) suggested that this variant results in a deletion of exons 9 and 10. Loss of these exons would be significant as this region contains the WD3/4 repeat region and is required for interaction with multiple proteins (UniProt).This variant has been observed in an individual with Fanconi Anemia who was found to harbor a second pathogenic variant in this gene, presumably on opposite alleles, as well at least two individuals with personal and/or family histories of breast cancer (Reid 2007, Fernandes 2014, Wong-Brown 2014). PALB2 c.3113+5G>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The guanine (G) nucleotide that is altered is conserved across species. Based on the currently available information, we consider PALB2 c.3113+5G>C to be a likely pathogenic variant.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785441 SCV000924013 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000231026 SCV000290864 uncertain significance Familial cancer of breast 2018-12-28 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the PALB2 gene. It does not directly change the encoded amino acid sequence of the PALB2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with breast cancer (PMID: 23824750, 24415441) and found to be heterozygous in a parent of an individual affected with Fanconi anemia type N, but the affected individual was not tested directly (PMID: 17200671). This variant is also known as IVS10+5G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 231961). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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