NM_000535.7(PMS2):c.2249G>A (p.Gly750Asp) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jun 18, 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:: RCV000212868.33

Allele description [Variation Report for NM_000535.7(PMS2):c.2249G>A (p.Gly750Asp)]

NM_000535.7(PMS2):c.2249G>A (p.Gly750Asp)

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.2249G>A (p.Gly750Asp)

HGVS:

NC_000007.14:g.5978622C>T
NG_008466.1:g.35485G>A
NM_000535.7:c.2249G>AMANE SELECT
NM_001322003.2:c.1844G>A
NM_001322004.2:c.1844G>A
NM_001322005.2:c.1844G>A
NM_001322006.2:c.2093G>A
NM_001322007.2:c.1931G>A
NM_001322008.2:c.1931G>A
NM_001322009.2:c.1844G>A
NM_001322010.2:c.1688G>A
NM_001322011.2:c.1316G>A
NM_001322012.2:c.1316G>A
NM_001322013.2:c.1676G>A
NM_001322014.2:c.2249G>A
NM_001322015.2:c.1940G>A
NP_000526.2:p.Gly750Asp
NP_001308932.1:p.Gly615Asp
NP_001308933.1:p.Gly615Asp
NP_001308934.1:p.Gly615Asp
NP_001308935.1:p.Gly698Asp
NP_001308936.1:p.Gly644Asp
NP_001308937.1:p.Gly644Asp
NP_001308938.1:p.Gly615Asp
NP_001308939.1:p.Gly563Asp
NP_001308940.1:p.Gly439Asp
NP_001308941.1:p.Gly439Asp
NP_001308942.1:p.Gly559Asp
NP_001308943.1:p.Gly750Asp
NP_001308944.1:p.Gly647Asp
LRG_161t1:c.2249G>A
LRG_161:g.35485G>A
NC_000007.13:g.6018253C>T
NM_000535.5:c.2249G>A
NM_000535.6:c.2249G>A
NR_136154.1:n.2336G>A
p.G750D

Protein change:

G439D

Links:

dbSNP: rs587779337

NCBI 1000 Genomes Browser:

rs587779337

Molecular consequence:

NM_000535.7:c.2249G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.2093G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1931G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1931G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1316G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1316G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1676G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2249G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1940G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2336G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000149588	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 18, 2024)	germline	clinical testing	Citation Link,
SCV001155025	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (May 1, 2019)	germline	clinical testing	Citation Link,
SCV005413771	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 10, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 18602922, 24027009, 25856668, 26116798, 26318770, 28888541, 30608896, 35223509, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000149588

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 18, 2024)

germline

clinical testing

Citation Link,

SCV001155025

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

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

Uncertain significance
(May 1, 2019)

germline

clinical testing

Citation Link,

SCV005413771

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 10, 2024)

germline

clinical testing

PubMed (9)
[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	2	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 (9)

Details of each submission

From GeneDx, SCV000149588.18

#	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 a damaging effect: reduced, though not deficient, MMR activity (PMID: 24027009, 30608896); 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: 18602922, 18709565, 21376568, 26318770, 26333163, 26116798, 20531397, 25856668, 28152038, 34371384, 31332305, 28888541, 30608896, 23435383, 33471991, 24027009, Fukui2011[Chapter], 37937776)

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001155025.27

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV005413771.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (9)

Description

PP3, PP4, PP5, PM2, PM3, PS3_supporting

#	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		2	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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