NM_002691.4(POLD1):c.410_413del (p.Val137fs) AND Colorectal cancer, susceptibility to, 10

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 13, 2023
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:: RCV001221075.6

Allele description [Variation Report for NM_002691.4(POLD1):c.410_413del (p.Val137fs)]

NM_002691.4(POLD1):c.410_413del (p.Val137fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

19q13.33

Genomic location:

Preferred name:

NM_002691.4(POLD1):c.410_413del (p.Val137fs)

HGVS:

NC_000019.10:g.50401867TCTG[1]
NG_033800.1:g.22545TCTG[1]
NM_001256849.1:c.410_413del
NM_001308632.1:c.410_413del
NM_002691.4:c.410_413delMANE SELECT
NP_001243778.1:p.Val137fs
NP_001295561.1:p.Val137fs
NP_002682.2:p.Val137fs
LRG_785t1:c.410_413del
LRG_785t2:c.410_413del
LRG_785:g.22545TCTG[1]
LRG_785p1:p.Val137fs
LRG_785p2:p.Val137fs
NC_000019.9:g.50905124TCTG[1]
NC_000019.9:g.50905124_50905127del
NM_002691.3:c.410_413del
NR_046402.2:n.451TCTG[1]

Protein change:

V137fs

Links:

dbSNP: rs2038649098

NCBI 1000 Genomes Browser:

rs2038649098

Molecular consequence:

NM_001256849.1:c.410_413del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001308632.1:c.410_413del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002691.4:c.410_413del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_046402.2:n.451TCTG[1] - 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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Mus musculus ubiquitin related modifier 1 (Urm1), mRNA
Mus musculus ubiquitin related modifier 1 (Urm1), mRNA
gi|146141213|ref|NM_026615.4|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001393098	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 13, 2023)	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

SCV001393098

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 13, 2023)

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, SCV001393098.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Val137Alafs*31) 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‚Äìassociated 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. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 949585). 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.

#	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: Jun 23, 2024

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