Submissions for variant NM_001166108.2(PALLD):c.1273A>T (p.Thr425Ser)

gnomAD frequency: 0.00299  dbSNP: rs140454899

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000116039	SCV000149948	uncertain significance	not provided	2014-03-10	criteria provided, single submitter	clinical testing	PALLD has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted PALLD c.1273A>T at the cDNA level, p.Thr425Ser (T425S) at the protein level, and results in the change of a Threonine to a Serine (ACT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALLD Thr425Ser was observed with an allele frequency of 0.6% (50/8600) in European Americans in the NHLBI Exome Sequencing Project, but is not frequent enough to be considered a polymorphism. This variant is a conservative amino acid substitution, altering a position that is well conserved throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. At 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	RCV000277356	SCV000448473	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	RCV000116039	SCV001154309	benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	PALLD: BS1, BS2
Ambry Genetics	RCV001357862	SCV002688622	likely benign	not specified	2022-09-16	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357862	SCV001553453	benign	not specified		no assertion criteria provided	clinical testing	The PALLD p.Thr425Ser variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs140454899), LOVD 3.0 and ClinVar (classified as uncertain significance by GeneDx and likely benign by Illumina). The variant was identified in control databases in 1184 of 268280 chromosomes (10 homozygous) at a frequency of 0.004413 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 146 of 9862 chromosomes (freq: 0.0148), South Asian in 359 of 30524 chromosomes (freq: 0.01176), Other in 39 of 6704 chromosomes (freq: 0.005817), European (non-Finnish) in 573 of 118148 chromosomes (freq: 0.00485), Latino in 46 of 35108 chromosomes (freq: 0.00131), African in 16 of 23610 chromosomes (freq: 0.000678) and European (Finnish) in 5 of 25076 chromosomes (freq: 0.000199), but was not observed in the East Asian population. The p.Thr425 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.