NM_000535.7(PMS2):c.2404C>T (p.Arg802Ter) AND Hereditary nonpolyposis colon cancer

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 24, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002265552.1

Allele description [Variation Report for NM_000535.7(PMS2):c.2404C>T (p.Arg802Ter)]

NM_000535.7(PMS2):c.2404C>T (p.Arg802Ter)

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.2404C>T (p.Arg802Ter)

HGVS:

NC_000007.14:g.5977629G>A
NG_008466.1:g.36478C>T
NM_000535.7:c.2404C>TMANE SELECT
NM_001322003.2:c.1999C>T
NM_001322004.2:c.1999C>T
NM_001322005.2:c.1999C>T
NM_001322006.2:c.2248C>T
NM_001322007.2:c.2086C>T
NM_001322008.2:c.2086C>T
NM_001322009.2:c.2032C>T
NM_001322010.2:c.1843C>T
NM_001322011.2:c.1471C>T
NM_001322012.2:c.1471C>T
NM_001322013.2:c.1831C>T
NM_001322014.2:c.2437C>T
NM_001322015.2:c.2095C>T
NP_000526.2:p.Arg802Ter
NP_001308932.1:p.Arg667Ter
NP_001308933.1:p.Arg667Ter
NP_001308934.1:p.Arg667Ter
NP_001308935.1:p.Arg750Ter
NP_001308936.1:p.Arg696Ter
NP_001308937.1:p.Arg696Ter
NP_001308938.1:p.Arg678Ter
NP_001308939.1:p.Arg615Ter
NP_001308940.1:p.Arg491Ter
NP_001308941.1:p.Arg491Ter
NP_001308942.1:p.Arg611Ter
NP_001308943.1:p.Arg813Ter
NP_001308944.1:p.Arg699Ter
LRG_161t1:c.2404C>T
LRG_161:g.36478C>T
NC_000007.13:g.6017260G>A
NM_000535.5:c.2404C>T
NM_000535.6:c.2404C>T
NR_136154.1:n.2448C>T
p.R802*

Protein change:

R491*; ARG802TER

Links:

OMIM: 600259.0004; dbSNP: rs63751466

NCBI 1000 Genomes Browser:

rs63751466

Molecular consequence:

NR_136154.1:n.2448C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000535.7:c.2404C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322003.2:c.1999C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322004.2:c.1999C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322005.2:c.1999C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322006.2:c.2248C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322007.2:c.2086C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322008.2:c.2086C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322009.2:c.2032C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322010.2:c.1843C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322011.2:c.1471C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322012.2:c.1471C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322013.2:c.1831C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322014.2:c.2437C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322015.2:c.2095C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary nonpolyposis colon cancer (HNPCC)
Synonyms:: Hereditary nonpolyposis colorectal cancer; Familial nonpolyposis colon cancer; Hereditary Nonpolyposis Colorectal Cancer Syndrome
Identifiers:: MONDO: MONDO:0018630; MedGen: C1333990; OMIM: PS120435

Recent activity

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NOL1/NOP2/sun family protein / antitermination NusB domain-containing protein [A...
NOL1/NOP2/sun family protein / antitermination NusB domain-containing protein [Arabidopsis thaliana]
gi|22331043|ref|NP_187924.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002548074	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 24, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 18602922, 15077197, 27435373, 26895986, 26110232, 28805995, 16507833, 34048176, 7629132 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002548074

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 24, 2022)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

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

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

Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.

De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT.

Am J Hum Genet. 2004 May;74(5):954-64. Epub 2004 Apr 7.

PubMed [citation]

PMID:: 15077197
PMCID:: PMC1181988

See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002548074.1

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

Description

Variant summary: PMS2 c.2404C>T (p.Arg802X) 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. The variant allele was found at a frequency of 2.7e-05 in 226074 control chromosomes. c.2404C>T has been reported in the literature in heterozygous individuals affected with Lynch syndrome-related cancers (example Senter_2008, Rosty_2016, Suerink_2016, van der Klift_2016, Manchana_2021). In the homozygous state, the variant has also been observed in multiple individuals with early onset brain tumors, leukemias, and lymphomas, often with cooccurring cafe-au-lait spots (example De Vos_2004, De Vos_2006, Andrianova_2017). These data indicate that the variant is very likely to be associated with disease. An endometrial carcinoma cell line with the variant was found to only generate a truncated protein product and was deficient in mismatch repair, suggesting a negative impact on protein function (Risinger_1995). 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

Last Updated: Oct 8, 2024

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