ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6331-8C>T

gnomAD frequency: 0.00007  dbSNP: rs769766403
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000760034 SCV000289455 likely benign not provided 2025-01-29 criteria provided, single submitter clinical testing
GeneDx RCV000760034 SCV000530592 likely benign not provided 2020-09-09 criteria provided, single submitter clinical testing
Counsyl RCV000228013 SCV000786441 likely benign Colorectal cancer, susceptibility to, 12 2018-05-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000420076 SCV000889784 benign not specified 2018-03-29 criteria provided, single submitter clinical testing
Mendelics RCV000228013 SCV001138856 likely benign Colorectal cancer, susceptibility to, 12 2019-05-28 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV002258860 SCV002536911 likely benign Hereditary cancer-predisposing syndrome 2021-01-13 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000420076 SCV004037825 benign not specified 2023-08-31 criteria provided, single submitter clinical testing Variant summary: POLE c.6331-8C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0001 in 248548 control chromosomes. The observed variant frequency is approximately 7.081 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. c.6331-8C>T has been reported in the literature in individuals affected with breast cancer (e.g. Guindalini_2022) and unspecified cancer (e.g. Bonache_2018). However, these reports do not provide unequivocal conclusions about association of the variant with Colorectal Cancer, and the authors classified the variants as uncertain significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30306255, 35264596). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences RCV004541435 SCV004780470 likely benign POLE-related disorder 2020-07-20 no assertion criteria provided clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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