NM_000535.7(PMS2):c.2249G>A (p.Gly750Asp) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 31, 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:: RCV000524463.12

Allele description [Variation Report for NM_000535.7(PMS2):c.2249G>A (p.Gly750Asp)]

NM_000535.7(PMS2):c.2249G>A (p.Gly750Asp)

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.2249G>A (p.Gly750Asp)

HGVS:

NC_000007.14:g.5978622C>T
NG_008466.1:g.35485G>A
NM_000535.7:c.2249G>AMANE SELECT
NM_001322003.2:c.1844G>A
NM_001322004.2:c.1844G>A
NM_001322005.2:c.1844G>A
NM_001322006.2:c.2093G>A
NM_001322007.2:c.1931G>A
NM_001322008.2:c.1931G>A
NM_001322009.2:c.1844G>A
NM_001322010.2:c.1688G>A
NM_001322011.2:c.1316G>A
NM_001322012.2:c.1316G>A
NM_001322013.2:c.1676G>A
NM_001322014.2:c.2249G>A
NM_001322015.2:c.1940G>A
NP_000526.2:p.Gly750Asp
NP_001308932.1:p.Gly615Asp
NP_001308933.1:p.Gly615Asp
NP_001308934.1:p.Gly615Asp
NP_001308935.1:p.Gly698Asp
NP_001308936.1:p.Gly644Asp
NP_001308937.1:p.Gly644Asp
NP_001308938.1:p.Gly615Asp
NP_001308939.1:p.Gly563Asp
NP_001308940.1:p.Gly439Asp
NP_001308941.1:p.Gly439Asp
NP_001308942.1:p.Gly559Asp
NP_001308943.1:p.Gly750Asp
NP_001308944.1:p.Gly647Asp
LRG_161t1:c.2249G>A
LRG_161:g.35485G>A
NC_000007.13:g.6018253C>T
NM_000535.5:c.2249G>A
NM_000535.6:c.2249G>A
NR_136154.1:n.2336G>A
p.G750D

Protein change:

G439D

Links:

dbSNP: rs587779337

NCBI 1000 Genomes Browser:

rs587779337

Molecular consequence:

NM_000535.7:c.2249G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.2093G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1931G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1931G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1316G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1316G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1676G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2249G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1940G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2336G>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
SCV000551998	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 31, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18602922, 26318770, 30608896, 24027009, 26116798, 28492532 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000551998

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 31, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

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

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

Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.

Lavoine N, Colas C, Muleris M, Bodo S, Duval A, Entz-Werle N, Coulet F, Cabaret O, Andreiuolo F, Charpy C, Sebille G, Wang Q, Lejeune S, Buisine MP, Leroux D, Couillault G, Leverger G, Fricker JP, Guimbaud R, Mathieu-Dramard M, Jedraszak G, Cohen-Hagenauer O, et al.

J Med Genet. 2015 Nov;52(11):770-8. doi: 10.1136/jmedgenet-2015-103299. Epub 2015 Aug 28. Review.

PubMed [citation]

PMID:: 26318770

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000551998.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 750 of the PMS2 protein (p.Gly750Asp). 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 constitutional mismatch repair deficiency syndrome (PMID: 18602922, 26318770, 30608896; https://hccpjournal.biomedcentral.com/articles/10.1186/1897-4287-9-S1-P38). 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: 91334). 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: 24027009, 26116798). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Nov 24, 2024

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