chr19-50399376-G-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_002691.4(POLD1):c.208G>T(p.Val70Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000887 in 1,612,884 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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POLD1 | NM_002691.4 | c.208G>T | p.Val70Phe | missense_variant | Exon 3 of 27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000375 AC: 57AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000303 AC: 76AN: 251112Hom.: 0 AF XY: 0.000332 AC XY: 45AN XY: 135742
GnomAD4 exome AF: 0.000940 AC: 1373AN: 1460572Hom.: 1 Cov.: 31 AF XY: 0.000914 AC XY: 664AN XY: 726652
GnomAD4 genome AF: 0.000374 AC: 57AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74490
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2Other:1
POLD1: BP4, BS1 -
The POLD1 c.208G>T; p.Val70Phe variant (rs147911699) is reported in the literature in an individual with colon cancer (Ghazani 2017). This variant is also reported in ClinVar (Variation ID: 225288). It is found in the general population with an overall allele frequency of 0.03% (89/282506 alleles) in the Genome Aggregation Database. The valine at codon 70 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Ghazani AA et al. Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study. Genet Med. 2017 Jul;19(7):787-795. -
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer (Ghazani 2017); This variant is associated with the following publications: (PMID: 28125075) -
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
BP4 -
Colorectal cancer, susceptibility to, 10 Uncertain:3Benign:1
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The POLD1 c.208G>T (p.Val70Phe) missense change has a maximum subpopulation frequency of 0.062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLD1-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
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not specified Uncertain:1Benign:2
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DNA sequence analysis of the POLD1 gene demonstrated a sequence change, c.208G>T, in exon 3 that results in an amino acid change, p.Val70Phe. This sequence change has been described in the gnomAD database with a frequency of 0.062% in the European sub-population (dbSNP rs147911699). The p.Val70Phe change has been identified in an individual with colon cancer (PMID: 28125075). The p.Val70Phe change affects a poorly conserved amino acid residue located in a domain of the POLD1 protein that is not known to be functional. The p.Val70Phe substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val70Phe change remains unknown at this time. -
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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. -
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Carcinoma of colon Uncertain:1
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Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome Uncertain:1
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POLD1-related disorder Benign:1
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). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at