NM_000535.7(PMS2):c.400C>T (p.Arg134Ter) AND Lynch syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 5, 2013
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000076872.14

Allele description [Variation Report for NM_000535.7(PMS2):c.400C>T (p.Arg134Ter)]

NM_000535.7(PMS2):c.400C>T (p.Arg134Ter)

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.400C>T (p.Arg134Ter)

Other names:

p.R134*:CGA>TGA

HGVS:

NC_000007.14:g.6002590G>A
NG_008466.1:g.11517C>T
NM_000535.7:c.400C>TMANE SELECT
NM_001322003.2:c.-6C>T
NM_001322004.2:c.-6C>T
NM_001322005.2:c.-6C>T
NM_001322006.2:c.400C>T
NM_001322007.2:c.82C>T
NM_001322008.2:c.82C>T
NM_001322009.2:c.-6C>T
NM_001322010.2:c.-6C>T
NM_001322011.2:c.-485C>T
NM_001322012.2:c.-485C>T
NM_001322013.2:c.-6C>T
NM_001322014.2:c.400C>T
NM_001322015.2:c.91C>T
NP_000526.2:p.Arg134Ter
NP_001308935.1:p.Arg134Ter
NP_001308936.1:p.Arg28Ter
NP_001308937.1:p.Arg28Ter
NP_001308943.1:p.Arg134Ter
NP_001308944.1:p.Arg31Ter
LRG_161t1:c.400C>T
LRG_161:g.11517C>T
NC_000007.13:g.6042221G>A
NM_000535.5:c.400C>T
NM_000535.6:c.400C>T
NR_136154.1:n.487C>T
p.Arg134Stop
p.Arg134X
p.R134*

Protein change:

R134*; ARG134TER

Links:

OMIM: 600259.0001; dbSNP: rs63750871

NCBI 1000 Genomes Browser:

rs63750871

Molecular consequence:

NM_001322003.2:c.-6C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322004.2:c.-6C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322005.2:c.-6C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322009.2:c.-6C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322010.2:c.-6C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322011.2:c.-485C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-485C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.-6C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NR_136154.1:n.487C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000535.7:c.400C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322006.2:c.400C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322007.2:c.82C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322008.2:c.82C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322014.2:c.400C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322015.2:c.91C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

Recent activity

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Homo sapiens zinc finger protein 232 (ZNF232), transcript variant 8, mRNA
Homo sapiens zinc finger protein 232 (ZNF232), transcript variant 8, mRNA
gi|2069852710|ref|NM_001395552.1|

Nucleotide
zinc finger protein 232 isoform c [Homo sapiens]
zinc finger protein 232 isoform c [Homo sapiens]
gi|1004170629|ref|NP_001307882.1|

Protein
Homo sapiens zinc finger protein 232 (ZNF232), transcript variant 7, mRNA
Homo sapiens zinc finger protein 232 (ZNF232), transcript variant 7, mRNA
gi|2069852708|ref|NM_001395551.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000108365	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV000713220	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 27, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9488480, 15077197, 26270727, 26318770, 7632227, 16426742, 26720728, 7661930, 26895986, 25741868
SCV000918060	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 13, 2018)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15845562, 24362816, 12714694, 21376568, 9488480, 15077197, 7661930 Citation Link,
SCV004839977	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 7661930, 15077197, 15845562, 18602922, 21376568, 26270727, 26318770, 26720728, 26895986, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	4	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Mismatch repair deficiency in phenotypically normal human cells.

Parsons R, Li GM, Longley M, Modrich P, Liu B, Berk T, Hamilton SR, Kinzler KW, Vogelstein B.

Science. 1995 May 5;268(5211):738-40.

PubMed [citation]

PMID:: 7632227

Overexpression of the DNA mismatch repair factor, PMS2, confers hypermutability and DNA damage tolerance.

Gibson SL, Narayanan L, Hegan DC, Buermeyer AB, Liskay RM, Glazer PM.

Cancer Lett. 2006 Dec 8;244(2):195-202. Epub 2006 Jan 19.

PubMed [citation]

PMID:: 16426742

See all PubMed Citations (15)

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000108365.3

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

Description

Coding sequence variation resulting in a stop codon

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000713220.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The p.Arg134X variant in PMS2 has been reported in at least 6 families (7 individuals) with PMS2-associated cancers (Parsons 1995 PMID: 7632227, Norquist 2016 PMID: 26720728, Rosty 2016 PMID: 26895986, LaDuca 2017 PMID: 28152038, Carter 2018 PMID: 30322717) and in the compound heterozygous state in 2 families (3 individuals) with constitutional mismatch repair disease (CMMRD; De Vos 2004 PMID: 15077197, Lavoine 2015 PMID: 26318770). It has also been identified in 1/128850 of European and 1/35440 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 134, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In vitro functional studies support an impact on protein function (Parsons 1995 PMID: 7632227, Nicolaides 1998 PMID: 9488480, Gibson 2006 PMID: 16426742). In addition, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000108365.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Moderate, PS3_Moderate.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918060.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: PMS2 c.400C>T (p.Arg134X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.697C>T, p.Gln233X; c.736_741delinsTGTGTGTGAAG, p.Pro246fsX3). The variant allele was found at a frequency of 8.2e-06 in 121392 control chromosomes. c.400C>T has been reported in the literature in individuals affected with Turcot syndrome who carry a second pathogenic variant (DeVos_2004) and in patients with Lynch Syndrome and colorectal cancer (Senter_2008, Durno_2005). These data indicate that the variant is likely to be associated with disease. Additionally, this variant was found to have a dominant negative effect in hamster fibroblast cells (Nicolaides_1998) but not in human fibroblast cells (Yamada_2003). However, the variant was found to abrogate the interaction with MLH1 (Nicolaides_1998), a known pathogenic mechanism. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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 All of Us Research Program, National Institutes of Health, SCV004839977.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (10)

Description

This variant changes 1 nucleotide in exon 5 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 18602922, 26720728, 26895986), and in an individual suspected of hereditary breast/ovarian cancer (PMID: 26270727). This variant has also been reported in individuals affected with constitutional mismatch repair deficiency (PMID: 7661930, 15077197, 15845562, 21376568, 26318770). This variant has been identified in 2/276892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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