NM_002691.4(POLD1):c.1561C>T (p.Arg521Trp) AND not provided

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jun 24, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003114670.3

Allele description [Variation Report for NM_002691.4(POLD1):c.1561C>T (p.Arg521Trp)]

NM_002691.4(POLD1):c.1561C>T (p.Arg521Trp)

Gene:
POLD1:DNA polymerase delta 1, catalytic subunit [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19q13.33
Genomic location:
Preferred name:
NM_002691.4(POLD1):c.1561C>T (p.Arg521Trp)
HGVS:
  • NC_000019.10:g.50407049C>T
  • NG_033800.1:g.27727C>T
  • NM_001256849.1:c.1561C>T
  • NM_001308632.1:c.1561C>T
  • NM_002691.4:c.1561C>TMANE SELECT
  • NP_001243778.1:p.Arg521Trp
  • NP_001295561.1:p.Arg521Trp
  • NP_002682.2:p.Arg521Trp
  • LRG_785t1:c.1561C>T
  • LRG_785t2:c.1561C>T
  • LRG_785:g.27727C>T
  • LRG_785p1:p.Arg521Trp
  • LRG_785p2:p.Arg521Trp
  • NC_000019.9:g.50910306C>T
  • NM_002691.2:c.1561C>T
  • NM_002691.3:c.1561C>T
  • NR_046402.2:n.1606C>T
Protein change:
R521W
Links:
dbSNP: rs1341055535
NCBI 1000 Genomes Browser:
rs1341055535
Molecular consequence:
  • NM_001256849.1:c.1561C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001308632.1:c.1561C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002691.4:c.1561C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_046402.2:n.1606C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003800139ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)		Uncertain significance
(Jun 24, 2022) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV003800139.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The POLD1 c.1561C>T; p.Arg521Trp variant (rs1341055535), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 469205). This variant is found in the general population with an overall allele frequency of 0.002% (5/281942 alleles) in the Genome Aggregation Database. The arginine at codon 521 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.471). This variant is located in the exonuclease domain (Palles 2013), and gene-disease association has been established for variants within the exonuclease domain (Seifert 2019). A different variant at this codon, p.Arg521Gln, is reported in a family with colorectal cancer, and in a cohort of individuals with lipodystrophy (Dron 2020, Mur 2020). Due to limited information, the clinical significance of the p.Arg521Trp variant is uncertain at this time. References: Dron JS et al. Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. BMC Med Genomics. 2020 Feb 10;13(1):23. PMID: 32041611. Mur P et al. Role of POLE and POLD1 in familial cancer. Genet Med. 2020 Dec;22(12):2089-2100. PMID: 32792570. Palles C et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013 Feb;45(2):136-44. PMID: 23263490. Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516. PMID: 30523343.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024