ClinVar Miner

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

gnomAD frequency: 0.00299  dbSNP: rs140454899
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Total submissions: 5
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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 RCV002371947 SCV002688622 likely benign Hereditary cancer-predisposing syndrome 2022-09-16 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.

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