NM_000535.7(PMS2):c.400C>T (p.Arg134Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 10, 2024
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:: RCV000115695.18

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:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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
SCV000187198	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 10, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15077197, 18602922, 19495563, 21376568, 26318770, 26720728, 26895986, 7661930 Citation Link,
SCV000686201	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 6, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 7661930, 15077197, 15845562, 18602922, 21376568, 26270727, 26318770, 26720728, 26895986, 25741868
SCV002530343	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Aug 19, 2021)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 26318770, 15077197, 18602922, 26895986, 26681312 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000187198

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 10, 2024)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV000686201

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 6, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV002530343

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Aug 19, 2021)

germline

curation

PubMed (5)
[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, curation

Citations

PubMed

Anaplastic oligoastrocytoma in Turcot syndrome.

Baehring J, Hui P, Piepmeier J, Bannykh SI.

J Neurooncol. 2009 Nov;95(2):293-298. doi: 10.1007/s11060-009-9928-y. Epub 2009 Jun 4.

PubMed [citation]

PMID:: 19495563

The molecular basis of Turcot's syndrome.

Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, et al.

N Engl J Med. 1995 Mar 30;332(13):839-47.

PubMed [citation]

PMID:: 7661930

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV000187198.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.R134* pathogenic mutation (also known as c.400C>T), located in coding exon 5 of the PMS2 gene, results from a C to T substitution at nucleotide position 400. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been identified in multiple individuals with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome caused by biallelic PMS2 mutations (Hamilton SR et al. N. Engl. J. Med. 1995 Mar;332:839-47; De Vos M et al. Am. J. Hum. Genet. 2004 May;74:954-64; Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8). This mutation has also been identified in multiple patients with Lynch syndrome-associated tumors that showed isolated loss of PMS2 protein expression on IHC (Senter L et al. Gastroenterology. 2008 Aug;135:419-28; Rosty C et al. BMJ Open. 2016 Feb;6:e010293). This alteration has also been detected in 1/1915 women with ovarian cancer, unselected for family history (Norquist BM et al. JAMA Oncol. 2016 Apr;2:482-90). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000686201.4

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

From Sema4, Sema4, SCV002530343.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

#	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: Sep 29, 2024

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