NM_000535.7(PMS2):c.2249G>A (p.Gly750Asp) AND PMS2-related disorder

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 11, 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:: RCV003398663.4

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:: PMS2-related disorder
Synonyms:: PMS2-related condition
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004111783	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004111783

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 11, 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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004111783.1

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

Description

The PMS2 c.2249G>A variant is predicted to result in the amino acid substitution p.Gly750Asp. This variant has been reported to occur with other PMS2 pathogenic variants in individuals with suspected mismatch repair deficiency syndrome and/or colorectal cancer (Senter et al. 2008. PubMed ID: 18602922; Lavoine et al. 2015. PubMed ID: 26318770; Table S1, Goodenberger et al. 2016. PubMed ID: 25856668). In at least one case, the variants were determined to be on opposite alleles (Senter et al. 2008. PubMed ID: 18602922). However, in at least two individuals with colorectal cancer there was a second pathogenic PMS2 variant present; however, phase was not determined (Supplemental Data, Bodo et al. 2015. PubMed ID: 26116798; Table S1, Goodenberger et al. 2016. PubMed ID: 25856668). Studies have shown that this variant, and PMS2 variants overall, were not significantly associated with an increased risk of ovarian or breast cancer (Table S7, Lilyquist et al. 2017. PubMed ID: 28888541; Supplemental Data, Lilyquist et al. 2017. PubMed ID: 28888541). Functional studies have shown that this variant impacts protein function (Drost et al. 2013. PubMed ID: 24027009; Table A2, Shuen et al. 2019. PubMed ID: 30608896). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6018253-C-T). This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to likely pathogenic to pathogenic. (https://www.ncbi.nlm.nih.gov/clinvar/variation/91334/); however, the majority of submitters favor likely pathogenic/pathogenic. Taken together, we interpret this variant 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 30, 2024

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