Submissions for variant NM_006231.4(POLE):c.1288G>A (p.Ala430Thr)

gnomAD frequency: 0.00006  dbSNP: rs140566004

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000226972	SCV000289249	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000226972	SCV000570198	likely benign	not provided	2021-06-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26302956, 28857155, 29855806, 26251183, 28873162)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000226972	SCV000601973	benign	not provided	2023-09-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000561918	SCV000671306	likely benign	Hereditary cancer-predisposing syndrome	2020-08-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000709277	SCV000838708	uncertain significance	Familial colorectal cancer	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000988953	SCV001138896	uncertain significance	Colorectal cancer, susceptibility to, 12	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000226972	SCV001148905	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561918	SCV002536740	benign	Hereditary cancer-predisposing syndrome	2021-01-26	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317168	SCV004021044	likely benign	not specified	2023-06-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003317168	SCV004243520	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907877	SCV004724815	likely benign	POLE-related condition	2019-03-08	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356034	SCV001551088	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The POLE p.Ala430Thr variant was identified in 2 of 2216 proband chromosomes (frequency: 0.0009) from individuals with nasopharyngeal carcinoma and advanced cancer (Mandelker 2017, Fountzilas 2018). The variant was identified in dbSNP (rs140566004) as “with uncertain significance allele” and ClinVar (classified as likely benign by Invitae, GeneDx and Quest Diagnostics and uncertain significance by Ambry Genetics and Mendelics). The variant was identified in control databases in 129 of 277,028 chromosomes (1 homozygous) at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: “Other” in 4 of 6466 chromosomes (freq: 0.0006), Latino in 4 of 34,418 chromosomes (freq: 0.0001), European in 9 of 126,672 chromosomes (freq: 0.00007), Finnish in 4 of 25,654 chromosomes (freq: 0.0002), and South Asian in 108 of 30,782 chromosomes (freq: 0.004). The variant was not observed in the African, Ashkenazi Jewish, and East Asian populations. The p.Ala430 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.