rs144143245
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The ENST00000440232.7(POLD1):c.2052G>C(p.Gln684His) variant causes a missense change. The variant allele was found at a frequency of 0.000678 in 1,613,510 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. Q684Q) has been classified as Likely benign.
Frequency
Consequence
ENST00000440232.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.2052G>C | p.Gln684His | missense_variant | 17/27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.2052G>C | p.Gln684His | missense_variant | 17/27 | 1 | NM_002691.4 | ENSP00000406046 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000427 AC: 65AN: 152270Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000440 AC: 110AN: 249976Hom.: 0 AF XY: 0.000428 AC XY: 58AN XY: 135428
GnomAD4 exome AF: 0.000704 AC: 1029AN: 1461122Hom.: 1 Cov.: 32 AF XY: 0.000658 AC XY: 478AN XY: 726898
GnomAD4 genome AF: 0.000427 AC: 65AN: 152388Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38AN XY: 74524
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:6
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 19, 2020 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLD1 p.Gln684His variant was identified in 1 of 2092 proband chromosomes (frequency: 0.0005) from individuals or families with colon cancer (Raskin 2017). The variant was also identified in dbSNP (ID: rs144143245) as "With other allele", ClinVar (classified as likely benign by Invitae, GeneDx; as uncertain significance by Ambry Genetics and six clinical laboratories), MutDB, and in LOVD 3.0 (1x). The variant was not identified in Cosmic database. The variant was identified in control databases in 120 of 276056 chromosomes at a frequency of 0.0004 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: African in 2 of 23958 chromosomes (freq: 0.00008), Other in 1 of 6448 chromosomes (freq: 0.0002), Latino in 11 of 34410 chromosomes (freq: 0.0003), European in 79 of 125698 chromosomes (freq: 0.0006), Ashkenazi Jewish in 4 of 10132 chromosomes (freq: 0.0004), Finnish in 23 of 25792 chromosomes (freq: 0.0009); it was not observed in the East Asian and South Asian populations. The p.Gln684 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 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | POLD1: BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The p.Gln684His variant in POLD1 has not been previously reported in individuals with colorectal cancer but has been identified in 49/65572 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144143245). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gln684His variant is uncertain. - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2021 | This variant is associated with the following publications: (PMID: 28608266, 29212164, 26648538, 29987844, 31285513, 31449058, 32041611) - |
Colorectal cancer, susceptibility to, 10 Uncertain:5Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Molecular Oncology Laboratory, Hospital Clínico San Carlos | Jun 01, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 22, 2023 | The POLD1 c.2052G>C (p.Gln684His) missense change has a maximum subpopulation frequency of 0.088% 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. This variant has been reported in individuals with colon cancer and/or colon polyposis (PMID: 29987844, 31285513, 29212164). 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jan 27, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 13, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Apr 06, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 08, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | True Health Diagnostics | Apr 27, 2018 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 10, 2017 | - - |
POLD1-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 25, 2024 | The POLD1 c.2052G>C variant is predicted to result in the amino acid substitution p.Gln684His. This variant has been reported in multiple individuals in the literature, such as: an individual with microsatellite stable colorectal cancer (Raskin et al. 2017. PubMed ID: 29212164), an individual with clinically suspected Lynch syndrome and loss of MSH2 in tumor tissue (the individual harbored additional variants; Kayser et al. 2018. PubMed ID: 29987844, Table S6, Patient 25), an individual with breast cancer (the individual harbored additional variants; Dominguez-Valentin et al. 2018. PubMed ID: 28608266, Table 2), an individual with attenuated adenomatous polyposis (Lorca et al. 2019. PubMed ID: 31285513, Table 2), and an individual with multiple primary cancer, who also carried several variants in other genes (Sylvester. 2021. PubMed ID: 34687117, patient MO111041 in Table S4 and Table S5). This variant is reported in 0.088% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/239269/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at