Submissions for variant NM_006231.4(POLE):c.6751T>C (p.Phe2251Leu)

gnomAD frequency: 0.00018  dbSNP: rs373768478

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001355508	SCV000543992	likely benign	not provided	2025-02-03	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000465392	SCV001775522	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-07-11	criteria provided, single submitter	clinical testing	The POLE c.6751T>C (p.Phe2251Leu) missense change has a maximum subpopulation frequency of 0.044% 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 POLE-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.
GeneDx	RCV001355508	SCV001982054	uncertain significance	not provided	2024-02-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with cervical, breast, and/or thyroid cancer (PMID: 35534704, 32098697); This variant is associated with the following publications: (PMID: 32098697, 36315513, 35534704)
Mendelics	RCV003492049	SCV002519160	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004943849	SCV005478845	likely benign	Hereditary cancer-predisposing syndrome	2024-08-23	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	RCV001355508	SCV001550419	uncertain significance	not provided		no assertion criteria provided	clinical testing	The POLE p.Phe2251Leu variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs373768478), LOVD 3.0 and in ClinVar (classified as a VUS for Colorectal cancer, susceptibility to, 12 by Invitae). The variant was also identified in control databases in 12 of 281748 chromosomes at a frequency of 0.000043 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 11 of 24946 chromosomes (freq: 0.000441) and Latino in 1 of 35376 chromosomes (freq: 0.000028), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, and South Asian populations. The p.Phe2251 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004533155	SCV004754370	uncertain significance	POLE-related disorder	2024-03-13	no assertion criteria provided	clinical testing	The POLE c.6751T>C variant is predicted to result in the amino acid substitution p.Phe2251Leu. This variant along with the POLE c.1597G>A (p.Val533Met), as well as pathogenic variants in PIK3CA and PTEN genes was found in dysplastic and invasive tumor components obtained from a cervical cancer specimen (Table 1, Vormittag-Nocito et al. 2020. PubMed ID: 32098697). Additional variants in other genes were also identified in both tumor components. This variant is reported in 0.044% of alleles in individuals of African descent in gnomADa and is interpreted has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/405677/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.