Submissions for variant NM_024675.4(PALB2):c.2514+3dup

gnomAD frequency: 0.00001  dbSNP: rs587781602

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129677	SCV000184476	likely benign	Hereditary cancer-predisposing syndrome	2020-06-16	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799318	SCV000938975	likely benign	Familial cancer of breast	2024-12-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129677	SCV001340936	uncertain significance	Hereditary cancer-predisposing syndrome	2020-05-12	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide at +3 position in intron 5 of the PALB2 gene. Splice site prediction tools suggest that this variant may not impact RNA splicing. However, this prediction has not been confirmed in published RNA studies. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/249934 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001849925	SCV002046276	uncertain significance	not provided	2024-08-25	criteria provided, single submitter	clinical testing	The PALB2 c.2514+3dup variant has not been reported in individuals with PALB2-related conditions in the published literature. The frequency of this variant in the general population, 0.000012 (3/249934 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect PALB2 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant.
Genetic Services Laboratory, University of Chicago	RCV001800428	SCV002071273	uncertain significance	not specified	2019-09-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001849925	SCV002107244	uncertain significance	not provided	2023-07-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001800428	SCV004100256	uncertain significance	not specified	2023-09-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000799318	SCV005689195	uncertain significance	Familial cancer of breast	2024-07-09	criteria provided, single submitter	clinical testing	The PALB2 c.2514+3dup intronic change results in a duplication at the +3 position of intron 5 of the PALB2 gene. Algorithms that predict the impact of sequence changes on splicing indicate that this variant likely does not affect splicing, but to our knowledge these predictions have not been confirmed by RNA studies. To our knowledge, this variant has not been reported as pathogenic in individuals with PALB2-associated conditions. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.