Submissions for variant NM_024675.4(PALB2):c.3025C>T (p.Pro1009Ser)

gnomAD frequency: 0.00001  dbSNP: rs764669864

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481367	SCV000568144	uncertain significance	not provided	2022-02-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal and family history of pancreatic cancer in published literature (Zhen 2015); This variant is associated with the following publications: (PMID: 24141787, 24485656, 19609323, 20871615, 25356972)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534054	SCV000633399	uncertain significance	Familial cancer of breast	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1009 of the PALB2 protein (p.Pro1009Ser). This variant is present in population databases (rs764669864, gnomAD 0.0009%). This missense change has been observed in individual(s) with a personal and/or family history of pancreatic cancer (PMID: 25356972). ClinVar contains an entry for this variant (Variation ID: 419928). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. 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.
Ambry Genetics	RCV000571996	SCV000663287	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-17	criteria provided, single submitter	clinical testing	The p.P1009S variant (also known as c.3025C>T), located in coding exon 10 of the PALB2 gene, results from a C to T substitution at nucleotide position 3025. The proline at codon 1009 is replaced by serine, an amino acid with similar properties. This variant was identified in 1/727 probands with pancreatic adenocarcinoma as well as a family history of pancreatic and/or other types of cancer (Zhen DB et al. Genet. Med. 2015 Jul;17:569-77). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000571996	SCV000686001	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 1009 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with pancreatic cancer (PMID: 25356972). This variant has also been identified in 1/251446 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.
Fulgent Genetics, Fulgent Genetics	RCV002489151	SCV002776278	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-03-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004527587	SCV004102901	uncertain significance	PALB2-related disorder	2023-10-09	criteria provided, single submitter	clinical testing	The PALB2 c.3025C>T variant is predicted to result in the amino acid substitution p.Pro1009Ser. This variant has been reported in an individual with pancreatic cancer (Table 2, Zhen et al. 2015. PubMed ID: 25356972; Table S2, Chaffee et al. 2018. PubMed ID: 28726808). This variant is reported in 1 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/16-23632771-G-A). It is interpreted as uncertain significance in Clinvar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/409395/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000534054	SCV005055043	uncertain significance	Familial cancer of breast	2023-11-17	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001030367	SCV001193328	uncertain significance	Pancreatic cancer, susceptibility to, 3	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.