Submissions for variant NM_006231.4(POLE):c.1270C>G (p.Leu424Val)

dbSNP: rs483352909

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000484685	SCV000543910	pathogenic	not provided	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 424 of the POLE protein (p.Leu424Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal adenomas and carcinomas (PMID: 23263490, 24501277, 25370038, 25529843, 27683556). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40046). 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 expected to disrupt POLE protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000484685	SCV000568806	pathogenic	not provided	2017-02-03	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted POLE c.1270C>G at the cDNA level, p.Leu424Val (L424V) at the protein level, and results in the change of a Leucine to a Valine (CTC>GTC). POLE Leu424Val has been observed in multiple individuals with either an attenuated polyposis phenotype or a history of early onset colorectal cancer, with de novo occurrence reported in two individuals (Palles 2013, Elsayed 2014, Chubb 2015). Additionally, Spier et al. (2014) found this variant to segregate with polyposis and/or colorectal cancer diagnoses in three families. While functional assays have not specifically interrogated POLE Leu424Val, the equivalent residue has been found to have an important role in exonuclease activity in both bacteriophage and yeast systems (Hogg 2004, Murphy 2006). POLE Leu424Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. POLE Leu424Val occurs at a position that is conserved across species and is located in the Exo IV motif of the Exonuclease Domain (Preston 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics	RCV000570294	SCV000671525	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-06	criteria provided, single submitter	clinical testing	The p.L424V pathogenic mutation (also known as c.1270C>G), located in coding exon 13 of the POLE gene, results from a C to G substitution at nucleotide position 1270. The leucine at codon 424 is replaced by valine, an amino acid with highly similar properties. This highly conserved residue is in the active site of the exonuclease domain of the POLE protein, and this alteration is predicted to affect the nuclear activity by distorting the packing of helices involved in the exonuclease active site (Palles C et al. Nat. Genet. 2013 Feb; 45(2):136-44). This mutation has been reported as one of the most commonly identified POLE mutations in familial colorectal cancer and polyposis patients. It has been shown to segregate with disease in multiple unrelated families and has not been reported in over six thousand controls or in population cohorts. In addition it has been reported as a de novo occurrence in two individuals (Spier I et al. Int. J. Cancer. 2015 Jul;137(2):320-31; Palles C et al. Nat. Genet. 2013 Feb; 45(2):136-44. Valle L et al. Hum. Mol. Genet. 2014 Jul; 23(13):3506-12. Elsayed FA et al. Eur. J. Hum. Genet. 2015 Aug; 23(8):1080-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000762892	SCV000893282	pathogenic	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420787	SCV001623148	pathogenic	Cystic fibrosis-gastritis-megaloblastic anemia syndrome	2021-05-10	criteria provided, single submitter	clinical testing	Variant summary: POLE c.1270C>G (p.Leu424Val) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251340 control chromosomes. c.1270C>G has been reported in the literature in multiple individuals affected with Colorectal Cancer or adenomas (e.g. Palles_2013, Chubb_2015, Elsayed_2015, Hamzaoui_2020), including at least one-de novo occurrence (e.g. Valle_2014), as well a co-segregation with disease in multiple families (e.g. Palles_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence indicating that the variant results in a significantly increased mutation rate as assessed by yeast fluctuation assays (e.g. Castellsague_2018, Hamzaoui_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic or risk factor. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000484685	SCV001748404	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000484685	SCV002550191	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000570294	SCV005901744	pathogenic	Hereditary cancer-predisposing syndrome	2024-12-22	criteria provided, single submitter	clinical testing	PS3_Moderate, PM1_Supporting, PM2_Supporting, PM6_Supporting, PP1_Strong, PP3, PP4_Strong c.1270C>G, located in exon 13 of the POLE gene, is predicted to result in the substitution of Leu by Val at codon 424, p.(Leu424Val). This variant is located at exonuclease domain and within the DNA binding cleft, and < 6Å from the DNA (PM1_Supporting). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.65 > 0.644) suggests a deleterious effect on protein function (PP3). Functional assays performed in yeast, mammalian and cell-free assays showed a reduced exonuclease repair function (PMIDs: 32792570, 30362666, 32938641, 29056344, 36915289) (PS3_Moderate). The variant has been identified de novo in a patient with polyposis (more than 10 adenomas) and CRC (PMID 24501277) (PM6_Supporting). In addition, this variant has been identified in 69 carriers from 16 families, showing cosegregation with POLE-associated clinical features (reviewed in PMID: 37848928; PP1_Strong). Whole Exome Sequencing in 6 tumours from TGCA/COSMIC database carrying this variant showed that at least two of them (endometrial and breast) have >5% of combined contribution of signature SBS10 (PMID: 37848928); the same characteristics were also found in a tumour from a germline carrier (PMID: 34594041) (PP4_Strong). This variant has been reported in the ClinVar database (7x pathogenic) and in the LOVD database (2x pathogenic, 6x likely pathogenic, 1x uncertain significance). Based on currently available information, the variant c.1270C>G should be considered a pathogenic variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005357246	SCV005915724	pathogenic	Familial colorectal cancer type X; Polymerase proofreading-related adenomatous polyposis	2023-06-23	criteria provided, single submitter	clinical testing
OMIM	RCV000033144	SCV000056926	risk factor	Colorectal cancer, susceptibility to, 12	2015-08-01	no assertion criteria provided	literature only