rs770403791
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_006231.4(POLE):āc.940T>Gā(p.Ser314Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S314S) has been classified as Likely benign.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.940T>G | p.Ser314Ala | missense_variant | 10/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.940T>G | p.Ser314Ala | missense_variant | 10/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000985 AC: 15AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000108 AC: 27AN: 250680Hom.: 0 AF XY: 0.0000812 AC XY: 11AN XY: 135536
GnomAD4 exome AF: 0.0000623 AC: 91AN: 1461076Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38AN XY: 726878
GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74362
ClinVar
Submissions by phenotype
Colorectal cancer, susceptibility to, 12 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 19, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Apr 22, 2021 | The POLE c.940T>G (p.Ser314Ala) missense change has a maximum non-founder population frequency of 0.0016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-133252760-A-C?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in an individual with early-onset colorectal cancer and a strong family history of colorectal cancer and familial adenomatous polyposis (PMID: 32567205) and an individual with endometrial carcinoma (PMID: 31866764). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 25, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 13, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2022 | The p.S314A variant (also known as c.940T>G), located in coding exon 10 of the POLE gene, results from a T to G substitution at nucleotide position 940. The serine at codon 314 is replaced by alanine, an amino acid with similar properties. This alteration was identified in a patient diagnosed with early onset colon cancer and reports numerous relatives diagnosed with colon cancer and/or familial adenomatous polyposis; of note, consanguinity is present in this family, but the degree of relationship was not documented and the genetic test results for other relatives were not provided (Siraj AK et al. Mol Genet Genomic Med. 2020 08;8:e1368). This alteration has also been identified in individuals diagnosed with ovarian, endometrial, prostate, and/or pancreatic cancers (Shirts BH et al. Genet. Med. 2016 Oct;18:974-81; Siraj AK et al. Cancer Cell Int. 2019 Dec;19:334; Song H et al. J Med Genet. 2021 05;58:305-313). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31866764, 24410847, 26845104, 27720647, 32567205) - |
Familial colorectal cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
POLE-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 07, 2023 | The POLE c.940T>G variant is predicted to result in the amino acid substitution p.Ser314Ala. This variant was reported in an individual with endometrial carcinoma (Siraj et al 2019. PubMed ID: 31866764) and in another individual with a personal history of early onset colorectal cancer and significant family history of colorectal cancer/familial adenomatous polyposis (Fig 1 in Siraj AK et al 2020. PubMed ID: 32567205). This variant is reported in 0.23% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is reported with conflicting interpretations of benign to variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/224589/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 09, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at