NM_000535.7(PMS2):c.325dup (p.Glu109fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 17, 2023
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:: RCV000536196.8

Allele description [Variation Report for NM_000535.7(PMS2):c.325dup (p.Glu109fs)]

NM_000535.7(PMS2):c.325dup (p.Glu109fs)

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.325dup (p.Glu109fs)

HGVS:

NC_000007.14:g.6003723dup
NG_008466.1:g.10389dup
NM_000535.7:c.325dupMANE SELECT
NM_001322003.2:c.-81dup
NM_001322004.2:c.-81dup
NM_001322005.2:c.-81dup
NM_001322006.2:c.325dup
NM_001322007.2:c.35+254dup
NM_001322008.2:c.35+254dup
NM_001322009.2:c.-81dup
NM_001322010.2:c.-81dup
NM_001322011.2:c.-560dup
NM_001322012.2:c.-560dup
NM_001322013.2:c.-81dup
NM_001322014.2:c.325dup
NM_001322015.2:c.-160dup
NP_000526.2:p.Glu109fs
NP_001308935.1:p.Glu109fs
NP_001308943.1:p.Glu109fs
LRG_161t1:c.325dup
LRG_161:g.10389dup
NC_000007.13:g.6043348_6043349insC
NC_000007.13:g.6043354dup
NM_000535.5:c.325dupG
NM_000535.6:c.325dup
NM_000535.6:c.325dupG
NR_136154.1:n.412dup

Protein change:

E109fs

Links:

dbSNP: rs587781716

NCBI 1000 Genomes Browser:

rs587781716

Molecular consequence:

NM_001322003.2:c.-81dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322004.2:c.-81dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322005.2:c.-81dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322009.2:c.-81dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322010.2:c.-81dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322011.2:c.-560dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-560dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.-81dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322015.2:c.-160dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000535.7:c.325dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322006.2:c.325dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322014.2:c.325dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322007.2:c.35+254dup - intron variant - [Sequence Ontology: SO:0001627]
NM_001322008.2:c.35+254dup - intron variant - [Sequence Ontology: SO:0001627]
NR_136154.1:n.412dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Klebsiella pneumoniae strain 53 contig336, whole genome shotgun sequence
Klebsiella pneumoniae strain 53 contig336, whole genome shotgun sequence
gi|1589949256|ref|NZ_SGOL01000335.1 |WGS:NZ_SGOL01|contig336

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000625635	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 17, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 26247049, 20205264, 21261604, 21376568, 24362816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000625635

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 17, 2023)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing analysis for exonic and intronic mismatch repair gene variants associated with Lynch syndrome confirms high concordance between minigene assays and patient RNA analyses.

van der Klift HM, Jansen AM, van der Steenstraten N, Bik EC, Tops CM, Devilee P, Wijnen JT.

Mol Genet Genomic Med. 2015 Jul;3(4):327-45. doi: 10.1002/mgg3.145. Epub 2015 Apr 23.

PubMed [citation]

PMID:: 26247049
PMCID:: PMC4521968

Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes.

Vaughn CP, Robles J, Swensen JJ, Miller CE, Lyon E, Mao R, Bayrak-Toydemir P, Samowitz WS.

Hum Mutat. 2010 May;31(5):588-93. doi: 10.1002/humu.21230.

PubMed [citation]

PMID:: 20205264

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000625635.7

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

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26247049). ClinVar contains an entry for this variant (Variation ID: 233300). This premature translational stop signal has been observed in individual(s) with colorectal cancer and/or constitutional mismatch repair deficiency (PMID: 20205264, 21261604). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs762485848, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Glu109Glyfs*30) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816).

#	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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