NM_000535.7(PMS2):c.1261C>T (p.Arg421Ter) AND Lynch syndrome

Germline classification:: Pathogenic (2 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:: RCV000076804.8

Allele description [Variation Report for NM_000535.7(PMS2):c.1261C>T (p.Arg421Ter)]

NM_000535.7(PMS2):c.1261C>T (p.Arg421Ter)

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.1261C>T (p.Arg421Ter)

HGVS:

NC_000007.14:g.5987504G>A
NG_008466.1:g.26603C>T
NM_000535.7:c.1261C>TMANE SELECT
NM_001322003.2:c.856C>T
NM_001322004.2:c.856C>T
NM_001322005.2:c.856C>T
NM_001322006.2:c.1105C>T
NM_001322007.2:c.943C>T
NM_001322008.2:c.943C>T
NM_001322009.2:c.856C>T
NM_001322010.2:c.700C>T
NM_001322011.2:c.328C>T
NM_001322012.2:c.328C>T
NM_001322013.2:c.688C>T
NM_001322014.2:c.1261C>T
NM_001322015.2:c.952C>T
NP_000526.2:p.Arg421Ter
NP_001308932.1:p.Arg286Ter
NP_001308933.1:p.Arg286Ter
NP_001308934.1:p.Arg286Ter
NP_001308935.1:p.Arg369Ter
NP_001308936.1:p.Arg315Ter
NP_001308937.1:p.Arg315Ter
NP_001308938.1:p.Arg286Ter
NP_001308939.1:p.Arg234Ter
NP_001308940.1:p.Arg110Ter
NP_001308941.1:p.Arg110Ter
NP_001308942.1:p.Arg230Ter
NP_001308943.1:p.Arg421Ter
NP_001308944.1:p.Arg318Ter
LRG_161t1:c.1261C>T
LRG_161:g.26603C>T
NC_000007.13:g.6027135G>A
NM_000535.5:c.1261C>T
NM_000535.6:c.1261C>T
NR_136154.1:n.1348C>T
p.Arg421*
p.Arg421X

Protein change:

R110*

Links:

dbSNP: rs587778617

NCBI 1000 Genomes Browser:

rs587778617

Molecular consequence:

NR_136154.1:n.1348C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000535.7:c.1261C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322003.2:c.856C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322004.2:c.856C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322005.2:c.856C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322006.2:c.1105C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322007.2:c.943C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322008.2:c.943C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322009.2:c.856C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322010.2:c.700C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322011.2:c.328C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322012.2:c.328C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322013.2:c.688C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322014.2:c.1261C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322015.2:c.952C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000108286	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV000271438	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 3, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26110232, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000108286

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v1.9)

Pathogenic
(Sep 5, 2013)

germline

research

Citation Link,

SCV000271438

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Mar 3, 2016)

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	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers.

Suerink M, van der Klift HM, Ten Broeke SW, Dekkers OM, Bernstein I, Capellá Munar G, Gomez Garcia E, Hoogerbrugge N, Letteboer TG, Menko FH, Lindblom A, Mensenkamp A, Moller P, van Os TA, Rahner N, Redeker BJ, Olderode-Berends MJ, Spruijt L, Vos YJ, Wagner A, Morreau H, Hes FJ, et al.

Genet Med. 2016 Apr;18(4):405-9. doi: 10.1038/gim.2015.83. Epub 2015 Jun 25. Erratum in: Genet Med. 2016 Jan;18(1):108. doi: 10.1038/gim.2015.178. Olderode, Maran [corrected to Olderode-Berends, M J W].

PubMed [citation]

PMID:: 26110232

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000108286.3

#	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, SCV000271438.3

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

Description

The p.Arg421X variant in PMS2 has been reported in one carrier with unspecified phenotype (Suerink 2015), and was absent from large population studies. This non sense variant leads to a premature termination codon at position 421, which is p redicted to lead to a truncated or absent protein. Heterozygous loss of function of the PMS2 gene is an established disease mechanism in Lynch syndrome. In summ ary, this variant meets our criteria to be classified as pathogenic for Lynch sy ndrome in an autosomal dominant manner based upon the predicted impact to the pr otein.

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

Last Updated: Sep 29, 2024

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