NM_000535.7(PMS2):c.137G>T (p.Ser46Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 31, 2024
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:: RCV000115657.26

Allele description [Variation Report for NM_000535.7(PMS2):c.137G>T (p.Ser46Ile)]

NM_000535.7(PMS2):c.137G>T (p.Ser46Ile)

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.137G>T (p.Ser46Ile)

Other names:

p.S46I:AGT>ATT

HGVS:

NC_000007.14:g.6005918C>A
NG_008466.1:g.8189G>T
NG_050738.1:g.1668C>A
NM_000535.7:c.137G>TMANE SELECT
NM_001322003.2:c.-269G>T
NM_001322004.2:c.-242-1860G>T
NM_001322005.2:c.-269G>T
NM_001322006.2:c.137G>T
NM_001322007.2:c.-79G>T
NM_001322008.2:c.-52-1860G>T
NM_001322009.2:c.-269G>T
NM_001322010.2:c.-242-1860G>T
NM_001322011.2:c.-748G>T
NM_001322012.2:c.-748G>T
NM_001322013.2:c.-269G>T
NM_001322014.2:c.137G>T
NM_001322015.2:c.-348G>T
NP_000526.2:p.Ser46Ile
NP_001308935.1:p.Ser46Ile
NP_001308943.1:p.Ser46Ile
LRG_161t1:c.137G>T
LRG_161:g.8189G>T
NC_000007.13:g.6045549C>A
NM_000535.5:c.137G>T
NM_000535.6:c.137G>T
NM_001322014.2:c.137G>T
NR_136154.1:n.224G>T
P54278:p.Ser46Ile
p.S46I

Protein change:

S46I; SER46ILE

Links:

UniProtKB: P54278#VAR_066838; OMIM: 600259.0012; dbSNP: rs121434629

NCBI 1000 Genomes Browser:

rs121434629

Molecular consequence:

NM_001322003.2:c.-269G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322005.2:c.-269G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322007.2:c.-79G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322009.2:c.-269G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322011.2:c.-748G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-748G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.-269G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322015.2:c.-348G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322004.2:c.-242-1860G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001322008.2:c.-52-1860G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001322010.2:c.-242-1860G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000535.7:c.137G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.137G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.137G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.224G>T - 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

Recent activity

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FAM182B family with sequence similarity 182 member B [Homo sapiens]
FAM182B family with sequence similarity 182 member B [Homo sapiens]
Gene ID:728882

Gene
Gene Links for Nucleotide (Select 1243457608) (1)
Gene
Taxonomy Links for Protein (Select 2500298239) (1)
Taxonomy
Mus musculus
Mus musculus
Transcriptional and epigenetic profiling of aged mouse SVZ-derived neural stem / progenitor cells

BioProject
BioProject Links for BioSample (Select 7407208) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184825	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 16619239, 17557300, 18602922, 21239990, 21376568, 22577899, 23709753, 24027009, 25871621, 26318770, 28286799 Citation Link,
SCV000267076	Vantari Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 26, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000686122	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 15256438, 16144131, 16619239, 17557300, 18602922, 21204794, 21376568, 22577899, 23709753, 24027009, 25345868, 28596308, 30702970, 31992580, 25741868
SCV004228118	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 12, 2023)	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

Integrated analysis of unclassified variants in mismatch repair genes.

Pastrello C, Pin E, Marroni F, Bedin C, Fornasarig M, Tibiletti MG, Oliani C, Ponz de Leon M, Urso ED, Della Puppa L, Agostini M, Viel A.

Genet Med. 2011 Feb;13(2):115-24. doi: 10.1097/GIM.0b013e3182011489.

PubMed [citation]

PMID:: 21239990

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

See all PubMed Citations (19)

Details of each submission

From Ambry Genetics, SCV000184825.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The c.137G>T (p.S46I) alteration is located in coding exon 2 of the PMS2 gene. This alteration results from a G to T substitution at nucleotide position 137, causing the serine (S) at amino acid position 46 to be replaced by an isoleucine (I). Based on data from gnomAD, the T allele has an overall frequency of 0.017% (48/277180) total alleles studied. The highest observed frequency was 0.031% (11/35326) of Latino alleles. This mutation has been identified in numerous individuals with a tumor exhibiting microsatellite instability and/or loss of PMS2 expression by immunohistochemistry and has been associated with a significant reduction in mismatch repair activity (Clendenning, 2006; Borras, 2013; Drost, 2013; Dudley, 2015). The p.S46I mutation has been reported in a homozygous state or in conjunction with a second PMS2 mutation in multiple individuals with phenotypes consistent with constitutional mismatch repair-deficiency (CMMR-D) (Auclair, 2007; Senter, 2008; Pastrello, 2011; Herkert, 2011; Lavoine, 2015; Rengifo-Cam, 2017). Data supports p.S46I as a founder mutation of likely European origin (Tomsic, 2013). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration 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

From Vantari Genetics, SCV000267076.1

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

#	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, SCV000686122.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

This missense variant replaces serine with isoleucine at codon 46 in the nucleotide binding pocket of the ATPase domain of the PMS2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant significantly impairs the mismatch repair activity of PMS2 protein (PMID: 23709753, 24027009). This variant has been reported in over 50 individuals affected with Lynch syndrome or Lynch syndrome-associated cancers (PMID: 15256438, 16619239, 18602922, 23709753, 28596308, 30702970, 31992580) and is thought to be a founder mutation in the Caucasian population (PMID: 22577899, 25345868). This variant has been reported in trans with pathogenic PMS2 variants in individuals affected with constitutional mismatch repair deficiency syndrome (PMID: 16144131, 17557300, 21204794, 21376568). This variant has been identified in 48/277180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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

From Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C., SCV004228118.1

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

#	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: May 19, 2024

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