NM_000535.7(PMS2):c.2113G>A (p.Glu705Lys) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 26, 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:: RCV000524457.14

Allele description [Variation Report for NM_000535.7(PMS2):c.2113G>A (p.Glu705Lys)]

NM_000535.7(PMS2):c.2113G>A (p.Glu705Lys)

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.2113G>A (p.Glu705Lys)

HGVS:

NC_000007.14:g.5982885C>T
NG_008466.1:g.31222G>A
NM_000535.7:c.2113G>AMANE SELECT
NM_001322003.2:c.1708G>A
NM_001322004.2:c.1708G>A
NM_001322005.2:c.1708G>A
NM_001322006.2:c.1957G>A
NM_001322007.2:c.1795G>A
NM_001322008.2:c.1795G>A
NM_001322009.2:c.1708G>A
NM_001322010.2:c.1552G>A
NM_001322011.2:c.1180G>A
NM_001322012.2:c.1180G>A
NM_001322013.2:c.1540G>A
NM_001322014.2:c.2113G>A
NM_001322015.2:c.1804G>A
NP_000526.2:p.Glu705Lys
NP_001308932.1:p.Glu570Lys
NP_001308933.1:p.Glu570Lys
NP_001308934.1:p.Glu570Lys
NP_001308935.1:p.Glu653Lys
NP_001308936.1:p.Glu599Lys
NP_001308937.1:p.Glu599Lys
NP_001308938.1:p.Glu570Lys
NP_001308939.1:p.Glu518Lys
NP_001308940.1:p.Glu394Lys
NP_001308941.1:p.Glu394Lys
NP_001308942.1:p.Glu514Lys
NP_001308943.1:p.Glu705Lys
NP_001308944.1:p.Glu602Lys
LRG_161t1:c.2113G>A
LRG_161:g.31222G>A
NC_000007.13:g.6022516C>T
NM_000535.5:c.2113G>A
NM_000535.6:c.2113G>A
NR_136154.1:n.2200G>A
P54278:p.Glu705Lys

Protein change:

E394K

Links:

UniProtKB: P54278#VAR_012974; dbSNP: rs267608161

NCBI 1000 Genomes Browser:

rs267608161

Molecular consequence:

NM_000535.7:c.2113G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1708G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1708G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1708G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1957G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1795G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1795G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1708G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1552G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1180G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1180G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1540G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2113G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1804G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2200G>A - 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
SCV000551983	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 26, 2023)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 16619239, 18602922, 23012243, 26110232, 26318770, 26681312, 26845104, 27601186, 27978560, 28466842, 16873062, 17029773, 17567544, 20176959, 20624957, 24027009, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000551983

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 26, 2023)

germline

clinical testing

PubMed (17)
[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

Long-range PCR facilitates the identification of PMS2-specific mutations.

Clendenning M, Hampel H, LaJeunesse J, Lindblom A, Lockman J, Nilbert M, Senter L, Sotamaa K, de la Chapelle A.

Hum Mutat. 2006 May;27(5):490-5. Erratum in: Hum Mutat. 2006 Nov;27(11):1155.

PubMed [citation]

PMID:: 16619239

The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.

Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, Lindblom A, Lagerstedt K, Thibodeau SN, Lindor NM, Young J, Winship I, Dowty JG, White DM, Hopper JL, Baglietto L, Jenkins MA, de la Chapelle A.

Gastroenterology. 2008 Aug;135(2):419-28. doi: 10.1053/j.gastro.2008.04.026. Epub 2008 May 2.

PubMed [citation]

PMID:: 18602922
PMCID:: PMC2759321

See all PubMed Citations (17)

Details of each submission

From Invitae, SCV000551983.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 705 of the PMS2 protein (p.Glu705Lys). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with clinical features of constitutional mismatch repair deficiency syndrome and Lynch syndrome (PMID: 16619239, 18602922, 23012243, 26110232, 26318770, 26681312, 26845104, 27601186, 27978560, 28466842; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 91328). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 16873062, 17029773, 17567544, 20176959, 20624957, 24027009). For these reasons, this variant has been 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: Apr 20, 2024

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