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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 4, 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:: RCV004003328.2

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]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004814296	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25871621, 29904176, 33693762, 34873870, 34964038, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004814296

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 4, 2024)

germline

clinical testing

PubMed (6)
[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	1	not provided	not provided	108544	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

Cancer prevention by aspirin in children with Constitutional Mismatch Repair Deficiency (CMMRD).

Leenders EKSM, Westdorp H, Brüggemann RJ, Loeffen J, Kratz C, Burn J, Hoogerbrugge N, Jongmans MCJ.

Eur J Hum Genet. 2018 Oct;26(10):1417-1423. doi: 10.1038/s41431-018-0197-0. Epub 2018 Jun 14. Review.

PubMed [citation]

PMID:: 29904176
PMCID:: PMC6138701

See all PubMed Citations (6)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004814296.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with PMS2-related cancer (PMID: 25871621, 33693762, 34873870). It has also been reported in the compound heterozygous state with another PMS2 variant in a child with constitutional mismatch repair deficiency (PMID: 29904176, 34964038). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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