ClinVar Miner

Submissions for variant NM_001166108.2(PALLD):c.1965-12616C>T (rs121908291)

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Total submissions: 3
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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 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 139 of the PALLD protein (p.Pro139Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs121908291, ExAC 0.01%). This variant has been reported to segregate with pancreatic cancer in a large, four-generation family (PMID: 17194196, 10454945, 11474289). This variant was present in 12 individuals diagnosed with either pancreatic adenocarcinoma (n=3) or histologically verified pre-cancerous dysplasia (n=9), while absent in the 16 unaffected family members. This variant was also reported in an individual affected with pancreatic cancer (1/84 high-risk cases), as well as in a healthy 91 year-old control individual (n=555) who had no first- or second-degree relative with cancer (PMID: 17415588). This variant is also known as 715C>T (Pro239Ser) in the literature due to the use of an alternate transcript. ClinVar contains an entry for this variant (Variation ID: 2572). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly-Damaging"; Align-GVGD: "Class C0"). However, experimental studies have shown that this missense change can disrupt the normal cellular cytoskeleton and can lead to enhanced cellular migration (PMID: 17194196). In summary, this variant segregates with disease (pancreatic cancer) in a single family, and disrupts protein function in vitro. However, this variant has also been reported in control individuals. The significance of this variant is also uncertain because this PALLD-specific condition is rare and multiple alternative PALLD mRNA transcripts and protein isoforms are expressed, confounding our understanding of this disease (PMID: 20436683). For these reasons, this change has been classified as a Variant of Uncertain Significance.
OMIM RCV000002681 SCV000022839 risk factor Pancreatic cancer 1 2007-06-01 no assertion criteria provided literature only

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