Submissions for variant NM_015450.3(POT1):c.1502A>G (p.Tyr501Cys)

dbSNP: rs1226322093

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001322388	SCV001513256	uncertain significance	Tumor predisposition syndrome 3	2022-08-23	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1022476). This variant has not been reported in the literature in individuals affected with POT1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 501 of the POT1 protein (p.Tyr501Cys).
Ambry Genetics	RCV002395708	SCV002700571	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-06	criteria provided, single submitter	clinical testing	The p.Y501C variant (also known as c.1502A>G), located in coding exon 11 of the POT1 gene, results from an A to G substitution at nucleotide position 1502. The tyrosine at codon 501 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV003433109	SCV004160995	uncertain significance	not provided	2022-05-01	criteria provided, single submitter	clinical testing	POT1: PM2, PP3