ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.3350+5G>A (rs587782566)

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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 RCV000131789 SCV000186838 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-25 criteria provided, single submitter clinical testing The c.3350+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 12 in the PALB2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been identified in the homozygous state in an individual with Fanconi Anemia features and RNA analysis showed skipping of coding exon 12 (Mori M et al. Haematologica. 2019 Oct;104:1962-1973). The BDGP splice prediction software does not produce a reliable prediction for the nearby native splice donor site, and the ESEfinder splice prediction software predicts a weakening in the native splice donor site efficiency. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000526519 SCV000633424 likely pathogenic Familial cancer of breast 2020-09-02 criteria provided, single submitter clinical testing This sequence change falls in intron 12 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 observed in an individual affected with Fanconi anemia (PMID: 30792206). ClinVar contains an entry for this variant (Variation ID: 142586). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this change results in the generation of two aberrant transcripts, one that leads to out-of-frame exon 12 skipping (p.G1068_S1186delinsVPGR), and the other that leads to the in-frame skipping of exons 11 and 12 together (p.N1039_R1117del) (PMID: 30890586). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mendelics RCV000131789 SCV000838994 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131789 SCV001358405 likely pathogenic Hereditary cancer-predisposing syndrome 2020-11-13 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +5 position of the intron 12 splice donor site of the PALB2 gene. Three RNA studies have reported aberrant mRNA transcripts in variant carriers that are predicted to disrupt the BRCA2 and RAD51 binding domain in the protein (PMID: 30890586, 32133419, 32238468). One of the aberrant transcript is also present in healthy controls, albeit at a lower average level than in carriers with this variant (PMID: 32133419). This variant has been reported in one individual affected with pancreatic cancer who also has a ATM truncation variant (PMID: 29731985) and in two individuals who underwent cancer genetic testing for suspicion of hereditary cancer (PMID: 32133419). The variant also has been observed in a homozygous carrier affected with Fanconi anemia (PMID: 32238468). This variant has been identified in 2/251408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease ( Based on the available evidence, this variant is classified as Likely Pathogenic.

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