Submissions for variant NM_001166108.2(PALLD):c.1965-12616C>T

gnomAD frequency: 0.00026  dbSNP: rs121908291

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160876	SCV000211564	benign	not specified	2014-02-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000168440	SCV000219137	uncertain significance	Pancreatic adenocarcinoma	2023-12-16	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 139 of the PALLD protein (p.Pro139Ser). This variant is present in population databases (rs121908291, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of PALLD-related conditions (PMID: 10454945, 11474289, 17194196, 17415588). It has also been observed to segregate with disease in related individuals. This variant is also known as 715C>T (Pro239Ser). ClinVar contains an entry for this variant (Variation ID: 2572). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PALLD function (PMID: 17194196). 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	RCV002326659	SCV002630395	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-04	criteria provided, single submitter	clinical testing	The p.P139S variant (also known as c.415C>T), located in coding exon 1 of the PALLD gene, results from a C to T substitution at nucleotide position 415. The proline at codon 139 is replaced by serine, an amino acid with similar properties. This alteration is also referred to as c.715C>T (p.P239S), based on an alternate transcript. This variant was reported to segregate with pancreatic cancer in a large family; the variant was present only in the 12 affected family members tested (3 with pancreatic cancer and 9 with pancreatic pre-cancer), but was absent from the 16 unaffected family members tested (Pogue-Geile KL et al. PLoS Med., 2006 Dec;3:e516). In another study, this alteration was identified in 1/84 high risk pancreatic adenocarcinoma cases but was also found in 1/555 unaffected controls (Zogopoulos G et al. Hum. Genet., 2007 Jun;121:635-7). In a functional study, cells with p.P139S (referred to as p.P239S by the authors) showed cytoskeletal changes, disrupted actin bundle assembly and increased migration. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003894786	SCV004711158	likely benign	PALLD-related condition	2024-02-26	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
OMIM	RCV000002681	SCV000022839	risk factor	Pancreatic cancer, susceptibility to, 1	2007-06-01	no assertion criteria provided	literature only