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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 12, 2024
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:: RCV000524467.8

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 colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

Recent activity

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Protease, serine, 12 neurotrypsin (motopsin) [Mus musculus]
Protease, serine, 12 neurotrypsin (motopsin) [Mus musculus]
gi|21619263|gb|AAH31429.1|

Protein
Spc24 SPC24 component of NDC80 kinetochore complex [Rattus norvegicus]
Spc24 SPC24 component of NDC80 kinetochore complex [Rattus norvegicus]
Gene ID:363028

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000551948	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 15077197, 16507833, 18602922, 25512458, 26110232, 26895986, 28805995, 2440087, 10037723, 21618646, 23012243, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000551948

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 12, 2024)

germline

clinical testing

PubMed (12)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

PMS2 mutations in childhood cancer.

De Vos M, Hayward BE, Charlton R, Taylor GR, Glaser AW, Picton S, Cole TR, Maher ER, McKeown CM, Mann JR, Yates JR, Baralle D, Rankin J, Bonthron DT, Sheridan E.

J Natl Cancer Inst. 2006 Mar 1;98(5):358-61.

PubMed [citation]

PMID:: 16507833

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000551948.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change creates a premature translational stop signal (p.Arg802*) in the PMS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the PMS2 protein. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This premature translational stop signal has been observed in individual(s) with Lynch syndrome-related cancers and childhood-onset hematological malignancies and brain tumors (PMID: 15077197, 16507833, 18602922, 25512458, 26110232, 26895986, 28805995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9237). This variant disrupts a region of the PMS2 protein in which other variant(s) (p.Met834Glyfs*17) have been determined to be pathogenic (PMID: 2440087, 10037723, 21618646, 23012243). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been 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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