Submissions for variant NM_006231.4(POLE):c.1021G>T (p.Ala341Ser)

gnomAD frequency: 0.00024  dbSNP: rs137860861

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657097	SCV000289235	likely benign	not provided	2025-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000657097	SCV000568953	uncertain significance	not provided	2024-12-05	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20951805, 26251183)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657097	SCV000601970	likely benign	not provided	2019-10-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573548	SCV000671374	likely benign	Hereditary cancer-predisposing syndrome	2020-08-06	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.
Mendelics	RCV000988954	SCV001138897	likely benign	Colorectal cancer, susceptibility to, 12	2024-04-09	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000573548	SCV000788158	uncertain significance	Hereditary cancer-predisposing syndrome	2017-10-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532915	SCV004116996	uncertain significance	POLE-related disorder	2024-03-20	no assertion criteria provided	clinical testing	The POLE c.1021G>T variant is predicted to result in the amino acid substitution p.Ala341Ser. To our knowledge, this variant has not been reported in the literature in association with POLE-related disease. This variant is reported in 0.096% of alleles in individuals of African descent in gnomAD and is present in the NHLBI GO Exome Sequencing Project cohort, which included in gnomAD (Table S5, Aoude et al. 2015. PubMed ID: 26251183). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/240372/). 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.