NM_000535.7(PMS2):c.325del (p.Glu109fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 25, 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:: RCV000129899.8

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

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

Gene:

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

Variant type:

Deletion

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

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

HGVS:

NC_000007.14:g.6003723del
NG_008466.1:g.10389del
NM_000535.7:c.325delMANE SELECT
NM_001322003.2:c.-81del
NM_001322004.2:c.-81del
NM_001322005.2:c.-81del
NM_001322006.2:c.325del
NM_001322007.2:c.35+254del
NM_001322008.2:c.35+254del
NM_001322009.2:c.-81del
NM_001322010.2:c.-81del
NM_001322011.2:c.-560del
NM_001322012.2:c.-560del
NM_001322013.2:c.-81del
NM_001322014.2:c.325del
NM_001322015.2:c.-160del
NP_000526.2:p.Glu109fs
NP_001308935.1:p.Glu109fs
NP_001308943.1:p.Glu109fs
LRG_161t1:c.325del
LRG_161:g.10389del
NC_000007.13:g.6043349del
NC_000007.13:g.6043354del
NM_000535.5:c.325delG
NM_000535.6:c.325del
NR_136154.1:n.412del
p.E109Kfs*3

Protein change:

E109fs

Links:

dbSNP: rs587781716

NCBI 1000 Genomes Browser:

rs587781716

Molecular consequence:

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

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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Lissotriton helveticus genome assembly, chromosome: 4_2
Lissotriton helveticus genome assembly, chromosome: 4_2
gi|2806713557|emb|OZ180049.1|

Nucleotide
Gene Links for dbVar (Select 51005098) (3)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184717	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 25, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001351216	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 5, 2019)	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

SCV000184717

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 25, 2022)

germline

clinical testing

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

Citation Link,

SCV001351216

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 5, 2019)

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

Citations

PubMed

Development, technical validation, and clinical application of a multigene panel for hereditary gastrointestinal cancer and polyposis.

Ricci MT, Volorio S, Signoroni S, Mariani P, Mariette F, Sardella D, Pensotti V, Vitellaro M.

Tumori. 2019 Aug;105(4):338-352. doi: 10.1177/0300891619847085. Epub 2019 May 8.

PubMed [citation]

PMID:: 31068090

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, SCV000184717.8

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

Description

The c.325delG pathogenic mutation, located in coding exon 4 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 325, causing a translational frameshift with a predicted alternate stop codon (p.E109Kfs*3). This mutation has been reported in an individual whose family meets Amsterdam criteria (Ricci MT et al. Tumori, 2019 Aug;105:338-352). 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, SCV001351216.2

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

Description

This variant deletes 1 nucleotide in exon 4 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. 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

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