NM_000535.7(PMS2):c.614A>C (p.Gln205Pro) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Sep 24, 2024
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:: RCV000485945.9

Allele description [Variation Report for NM_000535.7(PMS2):c.614A>C (p.Gln205Pro)]

NM_000535.7(PMS2):c.614A>C (p.Gln205Pro)

Gene:

PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.614A>C (p.Gln205Pro)

HGVS:

NC_000007.14:g.5999199T>G
NG_008466.1:g.14908A>C
NM_000535.7:c.614A>CMANE SELECT
NM_001322003.2:c.209A>C
NM_001322004.2:c.209A>C
NM_001322005.2:c.209A>C
NM_001322006.2:c.614A>C
NM_001322007.2:c.296A>C
NM_001322008.2:c.296A>C
NM_001322009.2:c.209A>C
NM_001322010.2:c.209A>C
NM_001322011.2:c.-320A>C
NM_001322012.2:c.-320A>C
NM_001322013.2:c.133-1776A>C
NM_001322014.2:c.614A>C
NM_001322015.2:c.305A>C
NP_000526.2:p.Gln205Pro
NP_001308932.1:p.Gln70Pro
NP_001308933.1:p.Gln70Pro
NP_001308934.1:p.Gln70Pro
NP_001308935.1:p.Gln205Pro
NP_001308936.1:p.Gln99Pro
NP_001308937.1:p.Gln99Pro
NP_001308938.1:p.Gln70Pro
NP_001308939.1:p.Gln70Pro
NP_001308943.1:p.Gln205Pro
NP_001308944.1:p.Gln102Pro
LRG_161t1:c.614A>C
LRG_161:g.14908A>C
NC_000007.13:g.6038830T>G
NM_000535.5:c.614A>C
NM_000535.6:c.614A>C
NR_136154.1:n.701A>C
p.Q205P

Protein change:

Q102P

Links:

dbSNP: rs587779342

NCBI 1000 Genomes Browser:

rs587779342

Molecular consequence:

NM_001322011.2:c.-320A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-320A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.133-1776A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000535.7:c.614A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.209A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.209A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.209A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.614A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.296A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.296A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.209A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.209A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.614A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.305A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.701A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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protein MIZU-KUSSEI 1-like [Cucurbita pepo subsp. pepo]
protein MIZU-KUSSEI 1-like [Cucurbita pepo subsp. pepo]
gi|1333113306|ref|XP_023530791.1|

Protein
protein NEN1 [Cucumis sativus]
protein NEN1 [Cucumis sativus]
gi|778655989|ref|XP_011660176.1|

Protein
uncharacterized protein At5g01610-like isoform X2 [Cucumis melo]
uncharacterized protein At5g01610-like isoform X2 [Cucumis melo]
gi|2316582477|ref|XP_008446412.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000567507	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Sep 24, 2024)	germline	clinical testing	Citation Link,
SCV001807510	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001954185	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - 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
SCV004219017	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Aug 3, 2023)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18602922, 24027009, 26247049, 31447099, 25980754, 27435373, 26333163, 26467025

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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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.

Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, Lindblom A, Lagerstedt K, Thibodeau SN, Lindor NM, Young J, Winship I, Dowty JG, White DM, Hopper JL, Baglietto L, Jenkins MA, de la Chapelle A.

Gastroenterology. 2008 Aug;135(2):419-28. doi: 10.1053/j.gastro.2008.04.026. Epub 2008 May 2.

PubMed [citation]

PMID:: 18602922
PMCID:: PMC2759321

Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene.

Drost M, Koppejan H, de Wind N.

Hum Mutat. 2013 Nov;34(11):1477-80. doi: 10.1002/humu.22426. Epub 2013 Sep 11.

PubMed [citation]

PMID:: 24027009
PMCID:: PMC3858603

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000567507.7

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

Description

Published functional studies demonstrate repair efficiency significantly higher than that of a pathogenic control but compromised when compared to wild-type (PMID: 24027009); Observed in individuals with a personal or family history of Lynch syndrome-associated tumors (PMID: 27435373, 34326862, 25980754); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20531397, 19283792, 26247049, 18709565, 21376568, 26333163, 27435373, 31447099, 36240479, 24027009, 34326862, 25980754, 37296477, 18602922, 11574484, Li_2024_Article, Plazzer2024[preprint], 37507074)

#	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, SCV001807510.1

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001954185.1

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004219017.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

In the published literature, this variant has been reported in individuals suspected of Lynch syndrome (PMIDs: 27435373 (2016), 25980754 (2015)). Functional studies showed inconclusive results regarding the variant's impact on protein function (PMID: 24027009 (2013)). The frequency of this variant in the general population, 0.000008 (2/251496 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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

Last Updated: Oct 8, 2024

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