chr12-132661055-C-T
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_006231.4(POLE):c.2974G>A(p.Ala992Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,614,130 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000338 AC: 85AN: 251454Hom.: 1 AF XY: 0.000338 AC XY: 46AN XY: 135902
GnomAD4 exome AF: 0.000136 AC: 199AN: 1461866Hom.: 2 Cov.: 31 AF XY: 0.000138 AC XY: 100AN XY: 727242
GnomAD4 genome AF: 0.000204 AC: 31AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74454
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4
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This variant is associated with the following publications: (PMID: 28873162, 31769227) -
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not specified Uncertain:1Benign:1
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Hereditary cancer-predisposing syndrome Benign:2
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. -
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Carcinoma of colon Uncertain:1
The POLE p.Ala992Thr variant was not identified in the literature nor was it identified in the MutDB database. The variant was identified in dbSNP (ID: rs115193764) “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: likely benign by Invitae and Ambry Genetics, and uncertain significance by GeneDx), Clinvitae (3x), Cosmic (1x in an endometrioid carcinoma), and in control databases in 88 (1 homozygous) of 277156 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 2 of 6456 chromosomes (freq: 0.0003), European Non-Finnish in 2 of 126672 chromosomes (freq: 0.00002), Ashkenazi Jewish in 10 (1 homozygous) of 10152 chromosomes (freq: 0.001), East Asian in 74 of 18868 chromosomes (freq: 0.004), while not observed in the African, Latino, European Finnish and South Asian populations. The p.Ala992 residue is conserved in mammals but not in more distantly related organisms; however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood that a Thr residue at this location impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at