Submissions for variant NM_006231.4(POLE):c.4187A>G (p.Asn1396Ser)

gnomAD frequency: 0.12807  dbSNP: rs5744934

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000434953	SCV000517999	benign	not specified	2015-11-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000434953	SCV000540083	benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency
Ambry Genetics	RCV000492397	SCV000581378	benign	Hereditary cancer-predisposing syndrome	2015-05-20	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588645	SCV000698673	benign	not provided	2016-05-19	criteria provided, single submitter	clinical testing	Variant summary: The POLE c.4187A>G (p.Asn1396Ser) variant involves the alteration of a conserved nucleotide with 2/3 in silico tools (SNPs&GO and MutationTaster not captured due to low reliability index and p-value) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 14342/121366 control chromosomes (1035 homozygotes, 1/8, freq.: 0.1181715), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic POLE variant of 1/70422 (0.0000142), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000434953	SCV000806775	benign	not specified	2016-10-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000588645	SCV001725688	benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001789334	SCV002031646	benign	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2021-10-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001789335	SCV002031647	benign	Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	2021-10-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588645	SCV002048262	benign	not provided	2023-11-21	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001517229	SCV004016678	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000588645	SCV005237229	benign	not provided		criteria provided, single submitter	not provided
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000492397	SCV005688889	benign	Hereditary cancer-predisposing syndrome	2024-12-23	criteria provided, single submitter	clinical testing	The missense variant NM_006231.4(POLE):c.4187A>G (p.Asn1396Ser) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 380215 as of 2024-12-05). The p.Asn1396Ser variant is predicted to introduce a novel acceptor splice site at this position by 3 of 4 splice site algorithms, but it's impact on the gene product is unknown. The p.Asn1396Ser missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.4187 in POLE is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Benign
Clinical Genetics, Academic Medical Center	RCV000434953	SCV001921963	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000434953	SCV001955310	benign	not specified		no assertion criteria provided	clinical testing