NM_000535.7(PMS2):c.1261C>T (p.Arg421Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 6, 2022
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:: RCV000223405.10

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]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000276002	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 6, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000821766	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001347955	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000276002

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 6, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000821766

GeneKor MSA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 1, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001347955

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 15, 2020)

germline

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000276002.7

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

Description

The p.R421* pathogenic mutation (also known as c.1261C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1261. This changes the amino acid from an arginine to a stop codon within coding exon 11. This pathogenic alteration was present in 1/130 European families with PMS2 mutations meeting either Bethesda criteria or "MSI-testing-indicated-by-a-pathologist" criteria (Suerink M et al. Genet. Med. 2016 Apr;18:405-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 GeneKor MSA, SCV000821766.2

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

Description

This is a point mutation replacing one nucleotide in the position 1261 of the PMS2 gene, leading in the replacement of Arginine with a termination stop codon in the position 421 of the PMS2 protein. The resulting protein is truncated and non functional. This particular variant has been described in international literature in families with colorectal cancer and/or Lynch syndrome (PMID: 23012243, PMID: 26110232). The mutation database ClinVar contains an entry for this variant (Variation ID: 91299).

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

From Color Diagnostics, LLC DBA Color Health, SCV001347955.2

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

Description

This variant changes 1 nucleotide in exon 11 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 not been identified 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

Last Updated: Sep 29, 2024

ClinVar

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