Submissions for variant NM_001166108.2(PALLD):c.909A>T (p.Arg303Ser)

gnomAD frequency: 0.00108  dbSNP: rs138897963

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000116059	SCV000149968	uncertain significance	not provided	2014-01-29	criteria provided, single submitter	clinical testing	PALLD has been only recently described in association with pancreatic cancer and the risks are not well understood. This variant is denoted PALLD c.909A>T at the cDNA level, p.Arg303Ser (R303S) at the protein level, and results in the change of an Arginine to a Serine (AGA>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALLD Arg303Ser was observed with an allele frequency of 0.1% in 1000 Genomes and 0.1% in Europeans in the NHLBI Exome Sequencing Project, which is not frequent enough to be considered a polymorphism. This variant is a semi-conservative substitution in which a positive polar amino acid is replaced with a neutral polar one, altering a position that is well conserved throughout evolution and is located within the lg-like C2-type 1 domain (UniProt, InterPro). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function, and predict this variant may weaken the nearby natural acceptor site. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the PALLD gene, remain unclear.
Illumina Laboratory Services, Illumina	RCV000271106	SCV000448470	benign	Pancreatic cancer, susceptibility to, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000116059	SCV004151808	benign	not provided	2022-03-01	criteria provided, single submitter	clinical testing	PALLD: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003952560	SCV004776171	likely benign	PALLD-related condition	2020-02-12	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).