NM_000535.7(PMS2):c.2003T>G (p.Ile668Arg) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 25, 2022
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:: RCV001241099.6

Allele description [Variation Report for NM_000535.7(PMS2):c.2003T>G (p.Ile668Arg)]

NM_000535.7(PMS2):c.2003T>G (p.Ile668Arg)

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.2003T>G (p.Ile668Arg)

HGVS:

NC_000007.14:g.5986762A>C
NG_008466.1:g.27345T>G
NM_000535.7:c.2003T>GMANE SELECT
NM_001322003.2:c.1598T>G
NM_001322004.2:c.1598T>G
NM_001322005.2:c.1598T>G
NM_001322006.2:c.1847T>G
NM_001322007.2:c.1685T>G
NM_001322008.2:c.1685T>G
NM_001322009.2:c.1598T>G
NM_001322010.2:c.1442T>G
NM_001322011.2:c.1070T>G
NM_001322012.2:c.1070T>G
NM_001322013.2:c.1430T>G
NM_001322014.2:c.2003T>G
NM_001322015.2:c.1694T>G
NP_000526.2:p.Ile668Arg
NP_001308932.1:p.Ile533Arg
NP_001308933.1:p.Ile533Arg
NP_001308934.1:p.Ile533Arg
NP_001308935.1:p.Ile616Arg
NP_001308936.1:p.Ile562Arg
NP_001308937.1:p.Ile562Arg
NP_001308938.1:p.Ile533Arg
NP_001308939.1:p.Ile481Arg
NP_001308940.1:p.Ile357Arg
NP_001308941.1:p.Ile357Arg
NP_001308942.1:p.Ile477Arg
NP_001308943.1:p.Ile668Arg
NP_001308944.1:p.Ile565Arg
LRG_161t1:c.2003T>G
LRG_161:g.27345T>G
NC_000007.13:g.6026393A>C
NM_000535.5:c.2003T>G
NR_136154.1:n.2090T>G

Protein change:

I357R

Links:

dbSNP: rs1562624877

NCBI 1000 Genomes Browser:

rs1562624877

Molecular consequence:

NM_000535.7:c.2003T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1598T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1598T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1598T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1847T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1685T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1685T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1598T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1442T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1070T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1070T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1430T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2003T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1694T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2090T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001414093	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 25, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25691505, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001414093

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 25, 2022)

germline

clinical testing

PubMed (2)
[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

A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype.

Li L, Hamel N, Baker K, McGuffin MJ, Couillard M, Gologan A, Marcus VA, Chodirker B, Chudley A, Stefanovici C, Durandy A, Hegele RA, Feng BJ, Goldgar DE, Zhu J, De Rosa M, Gruber SB, Wimmer K, Young B, Chong G, Tischkowitz MD, Foulkes WD.

J Med Genet. 2015 May;52(5):348-52. doi: 10.1136/jmedgenet-2014-102934. Epub 2015 Feb 17.

PubMed [citation]

PMID:: 25691505

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001414093.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ile668 amino acid residue in PMS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25691505). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 632955). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 668 of the PMS2 protein (p.Ile668Arg).

#	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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