NM_000535.7(PMS2):c.247_250dup (p.Thr84fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 25, 2020
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:: RCV002446929.2

Allele description [Variation Report for NM_000535.7(PMS2):c.247_250dup (p.Thr84fs)]

NM_000535.7(PMS2):c.247_250dup (p.Thr84fs)

Gene:

PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.247_250dup (p.Thr84fs)

HGVS:

NC_000007.14:g.6003972_6003975dup
NG_008466.1:g.10132_10135dup
NM_000535.7:c.247_250dupMANE SELECT
NM_001322003.2:c.-159_-156dup
NM_001322004.2:c.-159_-156dup
NM_001322005.2:c.-159_-156dup
NM_001322006.2:c.247_250dup
NM_001322007.2:c.32_35dup
NM_001322008.2:c.32_35dup
NM_001322009.2:c.-159_-156dup
NM_001322010.2:c.-159_-156dup
NM_001322011.2:c.-638_-635dup
NM_001322012.2:c.-638_-635dup
NM_001322013.2:c.-159_-156dup
NM_001322014.2:c.247_250dup
NM_001322015.2:c.-238_-235dup
NP_000526.2:p.Thr84fs
NP_001308935.1:p.Thr84fs
NP_001308936.1:p.Asn12_Asp13insTer
NP_001308937.1:p.Asn12_Asp13insTer
NP_001308943.1:p.Thr84fs
LRG_161t1:c.247_250dup
LRG_161:g.10132_10135dup
NC_000007.13:g.6043602_6043603insTTAA
NC_000007.13:g.6043603_6043606dup
NM_000535.5:c.247_250dupTTAA
NR_136154.1:n.334_337dup

Protein change:

T84fs

Links:

dbSNP: rs1554304940

NCBI 1000 Genomes Browser:

rs1554304940

Molecular consequence:

NM_001322003.2:c.-159_-156dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322004.2:c.-159_-156dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322005.2:c.-159_-156dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322009.2:c.-159_-156dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322010.2:c.-159_-156dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322011.2:c.-638_-635dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-638_-635dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.-159_-156dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322015.2:c.-238_-235dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000535.7:c.247_250dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322006.2:c.247_250dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322014.2:c.247_250dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322007.2:c.32_35dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001322008.2:c.32_35dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NR_136154.1:n.334_337dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001322007.2:c.32_35dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001322008.2:c.32_35dup - 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
SCV002733927	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 25, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25871621, 26110232, 27435373, 29345684, 29904176 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002733927

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 25, 2020)

germline

clinical testing

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

Citations

PubMed

Germline MLH1 Mutations Are Frequently Identified in Lynch Syndrome Patients With Colorectal and Endometrial Carcinoma Demonstrating Isolated Loss of PMS2 Immunohistochemical Expression.

Dudley B, Brand RE, Thull D, Bahary N, Nikiforova MN, Pai RK.

Am J Surg Pathol. 2015 Aug;39(8):1114-20. doi: 10.1097/PAS.0000000000000425.

PubMed [citation]

PMID:: 25871621

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

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002733927.2

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

Description

The c.247_250dupTTAA pathogenic mutation, located in coding exon 3 of the PMS2 gene, results from a duplication of TTAA at nucleotide position 247, causing a translational frameshift with a predicted alternate stop codon (p.T84Ifs*9). This mutation has been reported in multiple individuals with a personal history of endometrial cancer, with at least one patient's tumor demonstrating microsatellite instability (MSI-H) and loss of PMS2 expression on immunohistochemistry (IHC) (Dudley B et al. Am. J. Surg. Pathol., 2015 Aug;39:1114-20; van der Klift HM et al. Hum. Mutat., 2016 11;37:1162-1179; Roberts ME et al. Genet. Med., 2018 10;20:1167-1174). This mutation was reported 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 mutation has also been reported in the compound heterozygous state with another PMS2 mutation in a patient with constitutional mismatch repair deficiency (CMMRD) (Leenders EKSM et al. Eur. J. Hum. Genet., 2018 10;26:1417-1423). 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

Last Updated: Sep 29, 2024

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