NM_002691.4(POLD1):c.961G>A (p.Gly321Ser) AND not provided

Germline classification:: Uncertain significance (8 submissions)
Last evaluated:: Apr 2, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000657083.38

Allele description [Variation Report for NM_002691.4(POLD1):c.961G>A (p.Gly321Ser)]

NM_002691.4(POLD1):c.961G>A (p.Gly321Ser)

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.961G>A (p.Gly321Ser)

HGVS:

NC_000019.10:g.50402732G>A
NG_033800.1:g.23410G>A
NM_001256849.1:c.961G>A
NM_001308632.1:c.961G>A
NM_002691.4:c.961G>AMANE SELECT
NP_001243778.1:p.Gly321Ser
NP_001295561.1:p.Gly321Ser
NP_002682.2:p.Gly321Ser
LRG_785t1:c.961G>A
LRG_785t2:c.961G>A
LRG_785:g.23410G>A
LRG_785p1:p.Gly321Ser
LRG_785p2:p.Gly321Ser
NC_000019.9:g.50905989G>A
NM_002691.2:c.961G>A
NM_002691.3:c.961G>A
NM_002691.4:c.961G>A
NR_046402.2:n.1006G>A

Protein change:

G321S

Links:

dbSNP: rs41554817

NCBI 1000 Genomes Browser:

rs41554817

Molecular consequence:

NM_001256849.1:c.961G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001308632.1:c.961G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002691.4:c.961G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_046402.2:n.1006G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Homo sapiens XK related 3 (XKR3), transcript variant 5, mRNA
Homo sapiens XK related 3 (XKR3), transcript variant 5, mRNA
gi|1905076764|ref|NM_001386957.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000568613	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 2, 2024)	germline	clinical testing	Citation Link,
SCV000889703	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Dec 12, 2022)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 33193653, 33332384, 30827058, 25938944, 26648449, 26467025
SCV001152021	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Sep 1, 2022)	germline	clinical testing	Citation Link,
SCV001742598	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001807490	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001925623	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV004225433	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 13, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25938944, 30827058, 33193653, 35264596, 25741868
SCV005197225	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	4	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high incidence of cancer prone syndromes.

Byrjalsen A, Hansen TVO, Stoltze UK, Mehrjouy MM, Barnkob NM, Hjalgrim LL, Mathiasen R, Lautrup CK, Gregersen PA, Hasle H, Wehner PS, Tuckuviene R, Sackett PW, Laspiur AO, Rossing M, Marvig RL, Tommerup N, Olsen TE, Scheie D, Gupta R, Gerdes AM, Schmiegelow K, et al.

PLoS Genet. 2020 Dec;16(12):e1009231. doi: 10.1371/journal.pgen.1009231.

PubMed [citation]

PMID:: 33332384
PMCID:: PMC7787686

Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers.

Jansen AM, van Wezel T, van den Akker BE, Ventayol Garcia M, Ruano D, Tops CM, Wagner A, Letteboer TG, Gómez-García EB, Devilee P, Wijnen JT, Hes FJ, Morreau H.

Eur J Hum Genet. 2016 Jul;24(7):1089-92. doi: 10.1038/ejhg.2015.252. Epub 2015 Dec 9.

PubMed [citation]

PMID:: 26648449
PMCID:: PMC5070903

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000568613.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30827058, 30680046, 20951805, 25938944, 27320729, 26648449, 28188185, 29120461, 33193653, 33332384, 34326862, 35264596, 37088804)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000889703.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The frequency of this variant in the general population, 0.00066 (82/124328 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with colorectal polyps and colorectal cancer (PMIDs: 26648449 (2015), 25938944 (2015), 30827058 (2018), and 33193653 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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

From CeGaT Center for Human Genetics Tuebingen, SCV001152021.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

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

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001742598.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001807490.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001925623.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV004225433.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (5)

#	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		4	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005197225.1

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

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

Last Updated: Nov 10, 2024

Relating variation to medicine