Submissions for variant NM_006231.4(POLE):c.6518_6519del (p.Ser2173fs)

dbSNP: rs774417192

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679665	SCV000543918	uncertain significance	not provided	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the POLE gene (p.Ser2173Phefs*130). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 114 amino acid(s) of the POLE protein and extend the protein by 15 additional amino acid residues. This variant is present in population databases (rs774417192, gnomAD 0.009%). This frameshift has been observed in individual(s) with clinical features of FILS syndrome (PMID: 30503519). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 405609). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	RCV000679665	SCV000572069	uncertain significance	not provided	2018-07-26	criteria provided, single submitter	clinical testing	This deletion of two nucleotides in POLE is denoted c.6518_6519delCT at the cDNA level and p.Ser2173PhefsX130 (S2173FfsX130) at the protein level. The normal sequence, with the bases that are deleted in braces, is GACT[CT]TCCT. The deletion causes a frameshift which changes a Serine to a Phenylalanine at codon 2173 in exon 46 of the POLE gene, and results in an extension of the protein. The last 114 amino acids are replaced by 129 incorrect amino acids, disrupting a region that contains the Zinc finger domain (Tahirov 2009). Since the clinical significance of this extension is unclear, we consider c.6518_6519delCT to be a variant of uncertain significance.
Ambry Genetics	RCV000570450	SCV000671597	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-08	criteria provided, single submitter	clinical testing	The c.6518_6519delCT variant, located in coding exon 46 of the POLE gene, results from a deletion of two nucleotides at nucleotide positions 6518 to 6519, causing a translational frameshift with a predicted alternate stop codon (p.S2173Ffs*130). This alteration occurs at the 3' terminus of thePOLE gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 15 amino acids. This frameshift impacts the last 5%amino acids of the native protein. The exact functional effect of the altered amino acids is unknown. Based on the available evidence, the clinical significance of this variant remains unclear.
Counsyl	RCV000469022	SCV000785734	uncertain significance	Colorectal cancer, susceptibility to, 12	2017-11-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679665	SCV000806840	uncertain significance	not provided	2017-05-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509386	SCV002819617	uncertain significance	not specified	2022-12-02	criteria provided, single submitter	clinical testing	Variant summary: POLE c.6518_6519delCT (p.Ser2173PhefsX130) causes a frameshift which is expected to disrupt the last 114 amino acids and result in an extension of the protein. The variant allele was found at a frequency of 3.5e-05 in 230954 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6518_6519delCT has been reported in the literature in individuals affected with Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, Genital Anomalies, And Immunodeficiency( Logan_2018). This supporting data is currently insufficient to allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.