rs755709875
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_006231.4(POLE):āc.431A>Gā(p.His144Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000615 in 1,609,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000598 AC: 15AN: 251020Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135630
GnomAD4 exome AF: 0.0000590 AC: 86AN: 1457198Hom.: 0 Cov.: 31 AF XY: 0.0000622 AC XY: 45AN XY: 723750
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74340
ClinVar
Submissions by phenotype
not provided Uncertain:6
Observed in individuals with a personal or family history of breast/ovarian cancer, colorectal cancer and/or polyps cancer (PMID: 29212164, 32522261, 35980532); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32522261, 29212164, 35980532) -
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 144 of the POLE protein (p.His144Arg). This variant is present in population databases (rs755709875, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 405687). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLE protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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not specified Uncertain:2
The p.His144Arg variant in POLE has not been previously reported in individuals with colorectal cancer but has been reported by other clinical laboratories in C linVar (Variation ID: 405687). It has also been identified in 3/30758 South Asia n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; dbSNP rs755709875). Computational prediction tools and conservation analysis suggest that the p.His144Arg variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. In summary, t he clinical significance of the p.His144Arg variant is uncertain. ACMG/AMP Crite ria applied: PP3, PM2. -
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Colorectal cancer, susceptibility to, 12 Uncertain:1
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POLE-related disorder Uncertain:1
The POLE c.431A>G variant is predicted to result in the amino acid substitution p.His144Arg. This variant was identified in an individual affected with colorectal cancer whose tumor was microsatellite stable, but the variant was classified as uncertain (Table S3, Raskin et al. 2017. PubMed ID: 29212164). This variant was also described in an individual who underwent hereditary cancer testing; however, other variants of uncertain significance in other genes were also present (Velaquez et al. 2020. PubMed ID: 32522261, Table S1). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD and is classified in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/405687/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.H144R variant (also known as c.431A>G), located in coding exon 6 of the POLE gene, results from an A to G substitution at nucleotide position 431. The histidine at codon 144 is replaced by arginine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.H144R remains unclear. -
Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at