NM_002691.4(POLD1):c.2007-2del AND Colorectal cancer, susceptibility to, 10

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 9, 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:: RCV002846306.2

Allele description [Variation Report for NM_002691.4(POLD1):c.2007-2del]

NM_002691.4(POLD1):c.2007-2del

Gene:

POLD1:DNA polymerase delta 1, catalytic subunit [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

19q13.33

Genomic location:

Preferred name:

NM_002691.4(POLD1):c.2007-2del

HGVS:

NC_000019.10:g.50409517del
NG_033800.1:g.30195del
NM_001256849.1:c.2007-2del
NM_001308632.1:c.2085-2del
NM_002691.4:c.2007-2delMANE SELECT
LRG_785t1:c.2007-2del
LRG_785t2:c.2085-2del
LRG_785:g.30195del
NC_000019.9:g.50912774del

Molecular consequence:

NM_001256849.1:c.2007-2del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001308632.1:c.2085-2del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_002691.4:c.2007-2del - splice acceptor variant - [Sequence Ontology: SO:0001574]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003219441	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 9, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23263490, 23447401, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003219441

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 9, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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 Invitae, SCV003219441.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 affects a splice site in intron 16 of the POLD1 gene. Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLD1 protein are associated with an increased risk for colonic adenomatous polyps and colon cancer (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 polyposis or colon cancer.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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