NM_000535.7(PMS2):c.2033T>C (p.Ile678Thr) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 15, 2019
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:: RCV000217701.3

Allele description [Variation Report for NM_000535.7(PMS2):c.2033T>C (p.Ile678Thr)]

NM_000535.7(PMS2):c.2033T>C (p.Ile678Thr)

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.2033T>C (p.Ile678Thr)

HGVS:

NC_000007.14:g.5982965A>G
NG_008466.1:g.31142T>C
NM_000535.7:c.2033T>CMANE SELECT
NM_001322003.2:c.1628T>C
NM_001322004.2:c.1628T>C
NM_001322005.2:c.1628T>C
NM_001322006.2:c.1877T>C
NM_001322007.2:c.1715T>C
NM_001322008.2:c.1715T>C
NM_001322009.2:c.1628T>C
NM_001322010.2:c.1472T>C
NM_001322011.2:c.1100T>C
NM_001322012.2:c.1100T>C
NM_001322013.2:c.1460T>C
NM_001322014.2:c.2033T>C
NM_001322015.2:c.1724T>C
NP_000526.2:p.Ile678Thr
NP_001308932.1:p.Ile543Thr
NP_001308933.1:p.Ile543Thr
NP_001308934.1:p.Ile543Thr
NP_001308935.1:p.Ile626Thr
NP_001308936.1:p.Ile572Thr
NP_001308937.1:p.Ile572Thr
NP_001308938.1:p.Ile543Thr
NP_001308939.1:p.Ile491Thr
NP_001308940.1:p.Ile367Thr
NP_001308941.1:p.Ile367Thr
NP_001308942.1:p.Ile487Thr
NP_001308943.1:p.Ile678Thr
NP_001308944.1:p.Ile575Thr
LRG_161t1:c.2033T>C
LRG_161:g.31142T>C
NC_000007.13:g.6022596A>G
NM_000535.5:c.2033T>C
NM_000535.6:c.2033T>C
NR_136154.1:n.2120T>C
p.I678T

Protein change:

I367T

Links:

dbSNP: rs587782553

NCBI 1000 Genomes Browser:

rs587782553

Molecular consequence:

NM_000535.7:c.2033T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1628T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1628T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1628T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1877T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1715T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1715T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1628T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1472T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1100T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1100T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1460T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2033T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1724T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2120T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000279464	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Mar 20, 2017)	germline	clinical testing	Citation Link,
SCV001361928	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jul 15, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000279464

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Mar 20, 2017)

germline

clinical testing

Citation Link,

SCV001361928

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jul 15, 2019)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000279464.7

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

Description

This variant is denoted PMS2 c.2033T>C at the cDNA level, p.Ile678Thr (I678T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. PMS2 Ile678Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ile678Thr occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the nuclease domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Ile678Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361928.1

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

Description

Variant summary: PMS2 c.2033T>C (p.Ile678Thr) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1e-05 in 196332 control chromosomes, however the technology utilized for this dataset does not rule out pseudogene interference and thus cannot be relied upon to make any conclusions about variant significance for this gene. To our knowledge, no occurrence of c.2033T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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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