NM_002691.4(POLD1):c.2803G>A (p.Ala935Thr) AND Colorectal cancer, susceptibility to, 10

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 18, 2023
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:: RCV000465794.11

Allele description [Variation Report for NM_002691.4(POLD1):c.2803G>A (p.Ala935Thr)]

NM_002691.4(POLD1):c.2803G>A (p.Ala935Thr)

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.2803G>A (p.Ala935Thr)

HGVS:

NC_000019.10:g.50415809G>A
NG_033800.1:g.36487G>A
NM_001256849.1:c.2803G>A
NM_001308632.1:c.2881G>A
NM_002691.4:c.2803G>AMANE SELECT
NP_001243778.1:p.Ala935Thr
NP_001295561.1:p.Ala961Thr
NP_002682.2:p.Ala935Thr
LRG_785t1:c.2803G>A
LRG_785t2:c.2881G>A
LRG_785:g.36487G>A
LRG_785p1:p.Ala935Thr
LRG_785p2:p.Ala961Thr
NC_000019.9:g.50919066G>A
NM_002691.3:c.2803G>A
NM_002691.4:c.2803G>A

Protein change:

A935T

Links:

dbSNP: rs555452657

NCBI 1000 Genomes Browser:

rs555452657

Molecular consequence:

NM_001256849.1:c.2803G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001308632.1:c.2881G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002691.4:c.2803G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000547616	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 18, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000786410	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Apr 26, 2018)	unknown	clinical testing	Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000547616

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 18, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000786410

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Apr 26, 2018)

unknown

clinical testing

Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000547616.10

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 935 of the POLD1 protein (p.Ala935Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 408064). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLD1 protein function with a negative predictive value of 80%. 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

From Counsyl, SCV000786410.2

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

Last Updated: Mar 5, 2024

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