NM_000535.7(PMS2):c.400C>T (p.Arg134Ter) AND Lynch syndrome 4

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Nov 23, 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:: RCV000576870.8

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]

Condition(s)

Name:: Lynch syndrome 4 (LYNCH4)
Synonyms:: Colorectal cancer, hereditary nonpolyposis, type 4; Hereditary non-polyposis colorectal cancer, type 4
Identifiers:: MONDO: MONDO:0013699; MedGen: C1838333; Orphanet: 144; OMIM: 614337

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Mus musculus arylformamidase, mRNA (cDNA clone IMAGE:1246559), containing frame-...
Mus musculus arylformamidase, mRNA (cDNA clone IMAGE:1246559), containing frame-shift errors
gi|30962881|gb|BC052507.1|

Nucleotide
hypothetical protein [Bacillus atrophaeus]
hypothetical protein [Bacillus atrophaeus]
gi|489420124|ref|WP_003325878.1|

Protein
Rrh protein [Mus musculus]
Rrh protein [Mus musculus]
gi|28374197|gb|AAH46288.1|

Protein
DNA-binding transcription factor, zf-fungal binuclear cluster type Toe2 [Schizos...
DNA-binding transcription factor, zf-fungal binuclear cluster type Toe2 [Schizosaccharomyces pombe]
gi|6137066|emb|CAB59617.1|

Protein
RecName: Full=Tubulin alpha chain-like 3
RecName: Full=Tubulin alpha chain-like 3
gi|342187030|sp|Q3UX10.2|TBAL3_MOUS

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000677741	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Pathogenic (May 22, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26895986, 9488480, 15077197 Citation Link,
SCV000840047	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 19, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002762834	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 9, 2022)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004019879	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Apr 5, 2023)	unknown	clinical testing	Citation Link,
SCV004207883	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the Colon Cancer Family Registry Cohort.

Rosty C, Clendenning M, Walsh MD, Eriksen SV, Southey MC, Winship IM, Macrae FA, Boussioutas A, Poplawski NK, Parry S, Arnold J, Young JP, Casey G, Haile RW, Gallinger S, Le Marchand L, Newcomb PA, Potter JD, DeRycke M, Lindor NM, Thibodeau SN, Baron JA, et al.

BMJ Open. 2016 Feb 19;6(2):e010293. doi: 10.1136/bmjopen-2015-010293.

PubMed [citation]

PMID:: 26895986
PMCID:: PMC4762074

A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype.

Nicolaides NC, Littman SJ, Modrich P, Kinzler KW, Vogelstein B.

Mol Cell Biol. 1998 Mar;18(3):1635-41.

PubMed [citation]

PMID:: 9488480
PMCID:: PMC108878

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000677741.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000840047.1

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

Description

The c.400C>T (p.R134*) variant in the PMS2 gene is predicted to introduce a premature translation stop codon. This variant has been reported in the literature in multiple individuals with constitutional mismatch repair deficiency syndrome as well as in individuals with colorectal cancer, Lynch syndrome and ovarian cancer (PMID: 15077197, 18602922, 23012243, 26681312, 26895986). The c.400C>T (p.R134*) variant in the PMS2 gene is 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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV002762834.2

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

Description

PVS1, PS3, PS4_STR, PM2_SUP

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004019879.1

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

Description

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

#	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

From Baylor Genetics, SCV004207883.2

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

#	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: Sep 29, 2024

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