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NM_002691.4(POLD1):c.512_513insTGATGGC (p.Ile172fs) AND Colorectal cancer, susceptibility to, 10

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Oct 16, 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:
RCV001339972.8

Allele description [Variation Report for NM_002691.4(POLD1):c.512_513insTGATGGC (p.Ile172fs)]

NM_002691.4(POLD1):c.512_513insTGATGGC (p.Ile172fs)

Gene:
POLD1:DNA polymerase delta 1, catalytic subunit [Gene - OMIM - HGNC]
Variant type:
Insertion
Cytogenetic location:
19q13.33
Genomic location:
Preferred name:
NM_002691.4(POLD1):c.512_513insTGATGGC (p.Ile172fs)
HGVS:
  • NC_000019.10:g.50402047_50402048insTGATGGC
  • NG_033800.1:g.22725_22726insTGATGGC
  • NM_001256849.1:c.512_513insTGATGGC
  • NM_001308632.1:c.512_513insTGATGGC
  • NM_002691.4:c.512_513insTGATGGCMANE SELECT
  • NP_001243778.1:p.Ile172fs
  • NP_001295561.1:p.Ile172fs
  • NP_002682.2:p.Ile172fs
  • LRG_785t1:c.512_513insTGATGGC
  • LRG_785t2:c.512_513insTGATGGC
  • LRG_785:g.22725_22726insTGATGGC
  • LRG_785p1:p.Ile172fs
  • LRG_785p2:p.Ile172fs
  • NC_000019.9:g.50905300_50905301insTGGCTGA
  • NC_000019.9:g.50905304_50905305insTGATGGC
  • NR_046402.2:n.557_558insTGATGGC
Protein change:
I172fs
Links:
dbSNP: rs2038660307
NCBI 1000 Genomes Browser:
rs2038660307
Molecular consequence:
  • NM_001256849.1:c.512_513insTGATGGC - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001308632.1:c.512_513insTGATGGC - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_002691.4:c.512_513insTGATGGC - frameshift variant - [Sequence Ontology: SO:0001589]
  • NR_046402.2:n.557_558insTGATGGC - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Colorectal cancer, susceptibility to, 10
Synonyms:
COLORECTAL CANCER, SUSCEPTIBILITY TO, ON CHROMOSOME 19q; Colorectal cancer 10
Identifiers:
MONDO: MONDO:0012953; MedGen: C2675481; Orphanet: 220460; OMIM: 612591

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001533757Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Oct 16, 2022) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.

Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, Kemp Z, Spain SL, Guarino E, Salguero I, Sherborne A, Chubb D, Carvajal-Carmona LG, Ma Y, Kaur K, Dobbins S, Barclay E, Gorman M, Martin L, Kovac MB, Humphray S; CORGI Consortium.; et al.

Nat Genet. 2013 Feb;45(2):136-44. doi: 10.1038/ng.2503. Epub 2012 Dec 23. Erratum in: Nat Genet. 2013 Jun;45(6):713. Guarino Almeida, Estrella [corrected to Guarino, Estrella].

PubMed [citation]
PMID:
23263490
PMCID:
PMC3785128

Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers.

Briggs S, Tomlinson I.

J Pathol. 2013 Jun;230(2):148-53. doi: 10.1002/path.4185.

PubMed [citation]
PMID:
23447401
PMCID:
PMC3709119
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001533757.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

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. ClinVar contains an entry for this variant (Variation ID: 1036900). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile172Aspfs*82) in the POLD1 gene. Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLD1 protein are associated with PPAP (polymerase proofreading–associated polyposis) (PMID: 23263490, 23447401). However, loss-of-function variants that result in an absent or severely disrupted POLD1 protein, and missense variants outside the exonuclease domain, are unlikely to be associated with PPAP.

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

Last Updated: Sep 29, 2024