NM_006502.3(POLH):c.2074A>G (p.Thr692Ala) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 1, 2023
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:: RCV001090592.25

Allele description [Variation Report for NM_006502.3(POLH):c.2074A>G (p.Thr692Ala)]

NM_006502.3(POLH):c.2074A>G (p.Thr692Ala)

Gene:

POLH:DNA polymerase eta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p21.1

Genomic location:

Preferred name:

NM_006502.3(POLH):c.2074A>G (p.Thr692Ala)

HGVS:

NC_000006.12:g.43614489A>G
NG_009252.1:g.43349A>G
NM_001291969.2:c.1702A>G
NM_001291970.2:c.*758A>G
NM_006502.3:c.2074A>GMANE SELECT
NP_001278898.1:p.Thr568Ala
NP_006493.1:p.Thr692Ala
LRG_470:g.43349A>G
NC_000006.11:g.43582226A>G
NC_000006.11:g.43582226A>G
NM_006502.2:c.2074A>G

Protein change:

T568A

Links:

dbSNP: rs199562456

NCBI 1000 Genomes Browser:

rs199562456

Molecular consequence:

NM_001291970.2:c.*758A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001291969.2:c.1702A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006502.3:c.2074A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001246213	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Nov 1, 2023)	germline	clinical testing	Citation Link,
SCV003269433	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 7, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24130121, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001246213

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Nov 1, 2023)

germline

clinical testing

Citation Link,

SCV003269433

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 7, 2022)

germline

clinical testing

PubMed (2)
[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	yes	1	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

Correlation of phenotype/genotype in a cohort of 23 xeroderma pigmentosum-variant patients reveals 12 new disease-causing POLH mutations.

Opletalova K, Bourillon A, Yang W, Pouvelle C, Armier J, Despras E, Ludovic M, Mateus C, Robert C, Kannouche P, Soufir N, Sarasin A.

Hum Mutat. 2014 Jan;35(1):117-28.

PubMed [citation]

PMID:: 24130121

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001246213.26

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003269433.1

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

Description

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 692 of the POLH protein (p.Thr692Ala). This variant is present in population databases (rs199562456, gnomAD 0.05%). This missense change has been observed in individual(s) with POLH-related conditions (PMID: 24130121). ClinVar contains an entry for this variant (Variation ID: 870901). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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: Oct 20, 2024

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