NM_002691.4(POLD1):c.961G>A (p.Gly321Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Nov 3, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000564226.9

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]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000670900	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Nov 3, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25938944, 26648449 Citation Link,
SCV000788156	True Health Diagnostics	no assertion criteria provided	Uncertain significance (Sep 29, 2017)	germline	clinical testing
SCV002534716	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Sep 9, 2021)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 25938944, 30827058, 33193653, 26648449, 30680046, 33332384 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000670900

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Nov 3, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000788156

True Health Diagnostics

no assertion criteria provided

Uncertain significance
(Sep 29, 2017)

germline

clinical testing

SCV002534716

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Sep 9, 2021)

germline

curation

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

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, curation

Citations

PubMed

A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer.

Weren RD, Ligtenberg MJ, Kets CM, de Voer RM, Verwiel ET, Spruijt L, van Zelst-Stams WA, Jongmans MC, Gilissen C, Hehir-Kwa JY, Hoischen A, Shendure J, Boyle EA, Kamping EJ, Nagtegaal ID, Tops BB, Nagengast FM, Geurts van Kessel A, van Krieken JH, Kuiper RP, Hoogerbrugge N.

Nat Genet. 2015 Jun;47(6):668-71. doi: 10.1038/ng.3287. Epub 2015 May 4.

PubMed [citation]

PMID:: 25938944

Low frequency of POLD1 and POLE exonuclease domain variants in patients with multiple colorectal polyps.

Elsayed FA, Tops CMJ, Nielsen M, Ruano D, Vasen HFA, Morreau H, J Hes F, van Wezel T.

Mol Genet Genomic Med. 2019 Apr;7(4):e00603. doi: 10.1002/mgg3.603. Epub 2019 Mar 2.

PubMed [citation]

PMID:: 30827058
PMCID:: PMC6465667

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000670900.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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

From True Health Diagnostics, SCV000788156.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002534716.1

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

#	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: Nov 10, 2024

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