Submissions for variant NM_015450.3(POT1):c.526G>A (p.Gly176Arg)

gnomAD frequency: 0.00005  dbSNP: rs774576173

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567167	SCV000674409	likely benign	Hereditary cancer-predisposing syndrome	2024-10-04	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000652204	SCV000774072	uncertain significance	Tumor predisposition syndrome 3	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 176 of the POT1 protein (p.Gly176Arg). This variant is present in population databases (rs774576173, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of POT1-related conditions (PMID: 34193977). ClinVar contains an entry for this variant (Variation ID: 486140). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POT1 protein function with a negative predictive value of 80%. 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.
GeneDx	RCV001551221	SCV001771683	uncertain significance	not provided	2024-01-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in individuals with hematologic malignancies or epididymal papillary cystadenoma (PMID: 34193977, 35496736); This variant is associated with the following publications: (PMID: 25839328, 25710457, 36656928, 34193977, 28393830, 35496736)
Genetic Services Laboratory, University of Chicago	RCV001821690	SCV002070165	uncertain significance	not specified	2020-02-27	criteria provided, single submitter	clinical testing	DNA sequence analysis of the POT1 gene demonstrated a sequence change, c.526G>A, in exon 8 that results in an amino acid change, p.Gly176Arg. This sequence change does not appear to have been previously described in patients with POT1-related disorders and has been described in the gnomAD database with an overall population frequency of 0.0014% (dbSNP rs774576173). The p.Gly176Arg change affects a moderately/ conserved amino acid residue located in a domain of the POT1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly176Arg substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly176Arg change remains unknown at this time.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000652204	SCV004031241	uncertain significance	Tumor predisposition syndrome 3	2023-07-25	criteria provided, single submitter	clinical testing	The POT1 c.526G>A (p.Gly176Arg) missense change a maximum subpopulation frequency of 0.003% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POT1-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001821690	SCV005090802	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000652204	SCV001749928	not provided	Tumor predisposition syndrome 3		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 10-16-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.