VCV000239244.30 - ClinVar

NM_002691.4(POLD1):c.1562G>A (p.Arg521Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(6); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002691.4(POLD1):c.1562G>A (p.Arg521Gln)

Variation ID: 239244 Accession: VCV000239244.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.33 19: 50407050 (GRCh38) [ NCBI UCSC ] 19: 50910307 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 9, 2016	Sep 29, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002691.4:c.1562G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002682.2:p.Arg521Gln	missense
NM_001256849.1:c.1562G>A	NP_001243778.1:p.Arg521Gln	missense
NM_001308632.1:c.1562G>A	NP_001295561.1:p.Arg521Gln	missense
NR_046402.2:n.1607G>A		non-coding transcript variant
NC_000019.10:g.50407050G>A
NC_000019.9:g.50910307G>A
NG_033800.1:g.27728G>A
LRG_785:g.27728G>A
LRG_785t1:c.1562G>A	LRG_785p1:p.Arg521Gln
LRG_785t2:c.1562G>A	LRG_785p2:p.Arg521Gln

... more HGVS ... less HGVS

Protein change

R521Q

Other names

Canonical SPDI

NC_000019.10:50407049:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00009

The Genome Aggregation Database (gnomAD), exomes 0.00012

Exome Aggregation Consortium (ExAC) 0.00017

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038

Links

ClinGen: CA9596178 dbSNP: rs143076166 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
POLD1		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4946	4996

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Colorectal cancer, susceptibility to, 10	Uncertain significance (3)	criteria provided, single submitter	Jan 31, 2024	RCV000234172.15
Colorectal cancer	Uncertain significance (1)	criteria provided, single submitter	Oct 1, 2016	RCV000590937.3
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Feb 19, 2022	RCV000574111.8
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 11, 2024	RCV000657104.11
not specified	Uncertain significance (1)	criteria provided, single submitter	Jul 31, 2024	RCV002267983.6
Familial colorectal cancer Mandibular hypoplasia-deafness-progeroid syndrome	not provided (1)	no classification provided	-	RCV003483586.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Oct 01, 2016)	criteria provided, single submitter (Amendola et al. (Genome Res. 2015)) Method: research	Colorectal cancer Affected status: yes Allele origin: germline	CSER _CC_NCGL, University of Washington Study: CSER - NEXT Medicine variant annotation Accession: SCV000700093.1 First in ClinVar: Mar 23, 2018 Last updated: Mar 23, 2018	Comment: Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 37 year old female diagnosed with colon … (more) Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 37 year old female diagnosed with colon cancer at age 36. Patient also has a likely pathogenic variant in MSH2. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. (less)
Uncertain significance (Jul 24, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000601882.3 First in ClinVar: Oct 09, 2016 Last updated: Jan 01, 2022	Publications: PubMed (1) PubMed: 26133394
Uncertain significance (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Colorectal cancer, susceptibility to, 10 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000287525.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 28492532‚ 26133394 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 521 of the POLD1 protein (p.Arg521Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 521 of the POLD1 protein (p.Arg521Gln). This variant is present in population databases (rs143076166, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 26133394). ClinVar contains an entry for this variant (Variation ID: 239244). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLD1 protein function with a negative predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. (less)
Likely benign (Jan 16, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000670976.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 26133394 Comment: 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 … (more) 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. (less)
Uncertain significance (Feb 11, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000293778.16 First in ClinVar: Jul 24, 2016 Last updated: Sep 29, 2024	Comment: Observed in individuals with colorectal cancer (PMID: 26133394, 32792570); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In … (more) Observed in individuals with colorectal cancer (PMID: 26133394, 32792570); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 32792570, 26133394, 32041611, 33809179, Andrianova2023[preprint], 20951805, 37848928) (less)
Uncertain significance (Feb 19, 2022)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002534594.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The POLD1 c.1562G>A (p.R521Q) variant has been reported in at least two individuals with colorectal cancer (PMID: 32792570, 26133394). It was observed in 29/128564 chromosomes … (more) The POLD1 c.1562G>A (p.R521Q) variant has been reported in at least two individuals with colorectal cancer (PMID: 32792570, 26133394). It was observed in 29/128564 chromosomes of the Non-Finnish European subpopulation, with no homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 239244). In silico tools suggest the impact of the variant on protein function is inconclusive though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (2) PubMed: 32792570‚ 26133394
Uncertain significance (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002551919.5 First in ClinVar: Jul 28, 2022 Last updated: Aug 04, 2024
Uncertain significance (Sep 26, 2015)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, susceptibility to, 10 Affected status: no Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Study: CSER-NextGen Accession: SCV000493784.1 First in ClinVar: Jan 23, 2017 Last updated: Jan 23, 2017
Uncertain significance (Nov 17, 2017)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	True Health Diagnostics Accession: SCV000788130.1 First in ClinVar: Jan 01, 2018 Last updated: Jan 01, 2018
not provided (-)	no classification provided Method: phenotyping only	Colorectal cancer, susceptibility to, 10 Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002075202.1 First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022	Comment: Variant interpreted as Uncertain significance and reported on 03-18-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the … (more) Variant interpreted as Uncertain significance and reported on 03-18-2019 by Lab or GTR ID 26957. 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. (less) Clinical Features: Melanoma (present) , Neoplasm of the skin (present) , Bipolar affective disorder (present) , Psychotic disorder (present) , Gingivitis (present) Indication for testing: Diagnostic Age: 20-29 years Sex: female Ethnicity/Population group: Caucasians Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2019-03-18 Testing laboratory interpretation: Uncertain significance
not provided (-)	no classification provided Method: phenotyping only	Familial colorectal cancer Mandibular hypoplasia-deafness-progeroid syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV004228825.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Comment: Variant interpreted as Uncertain significance and reported on 01-12-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more) Variant interpreted as Uncertain significance and reported on 01-12-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Abnormal lens morphology (present) , Abnormality of vision (present) , Vertigo (present) , Vascular dilatation (present) , Abnormality of the cardiovascular system (present) , Decreased … (more) Abnormal lens morphology (present) , Abnormality of vision (present) , Vertigo (present) , Vascular dilatation (present) , Abnormality of the cardiovascular system (present) , Decreased pulmonary function (present) , Respiratory insufficiency (present) , Abnormal pattern of respiration (present) , Autoimmunity (present) , Abnormal intestine morphology (present) , Abnormality of the liver (present) , Abnormal large intestine morphology (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormal morphology of the pelvis musculature (present) , Abnormal curvature of the vertebral column (present) , Abnormality of the bladder (present) , Abnormal renal physiology (present) , Abnormal renal morphology (present) , Abnormality of the urethra (present) , Abnormality of urine homeostasis (present) , Abnormality of the nervous system (present) , Abnormality of coordination (present) , EEG abnormality (present) , Movement disorder (present) , Anxiety (present) , Bipolar affective disorder (present) , Depression (present) , Pregnancy history (present) (less) Indication for testing: Presymptomatic, Family Testing Age: 60-69 years Sex: female Method: Gene Panel Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2021-01-12 Testing laboratory interpretation: Uncertain significance
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Comment:

Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 37 year old female diagnosed with colon cancer at age 36. Patient also has a likely pathogenic variant in MSH2. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 521 of the POLD1 protein (p.Arg521Gln). This variant is present in population databases (rs143076166, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 26133394). ClinVar contains an entry for this variant (Variation ID: 239244). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLD1 protein function with a negative predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.

Comment:

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.

Comment:

Observed in individuals with colorectal cancer (PMID: 26133394, 32792570); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 32792570, 26133394, 32041611, 33809179, Andrianova2023[preprint], 20951805, 37848928)

Comment:

Variant interpreted as Uncertain significance and reported on 03-18-2019 by Lab or GTR ID 26957. 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.

Comment:

Variant interpreted as Uncertain significance and reported on 01-12-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Role of POLE and POLD1 in familial cancer.	Mur P	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32792570
POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance.	Bellido F	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26133394

Text-mined citations for rs143076166 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_002691.4(POLD1):c.1562G>A (p.Arg521Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs143076166 ...