NM_000535.7(PMS2):c.2249G>A (p.Gly750Asp) AND Lynch syndrome 4

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Sep 22, 2023
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:: RCV001253062.9

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:: Lynch syndrome 4 (LYNCH4)
Synonyms:: Colorectal cancer, hereditary nonpolyposis, type 4; Hereditary non-polyposis colorectal cancer, type 4
Identifiers:: MONDO: MONDO:0013699; MedGen: C1838333; Orphanet: 144; OMIM: 614337

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002762836	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 9, 2022)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004041161	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 5, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004187598	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Sep 22, 2023)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24027009, 18602922, 30608896, 26318770 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002762836

Centre for Mendelian Genomics, University Medical Centre Ljubljana

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 9, 2022)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV004041161

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 5, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004187598

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Likely pathogenic
(Sep 22, 2023)

unknown

clinical testing

PubMed (4)
[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	no	not provided	not provided	not provided	not provided	not provided	research
not provided	unknown	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

Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene.

Drost M, Koppejan H, de Wind N.

Hum Mutat. 2013 Nov;34(11):1477-80. doi: 10.1002/humu.22426. Epub 2013 Sep 11.

PubMed [citation]

PMID:: 24027009
PMCID:: PMC3858603

See all PubMed Citations (5)

Details of each submission

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV002762836.2

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

Description

PS4_STR, PS3, PM2_SUP

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004041161.1

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

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

From Myriad Genetics, Inc., SCV004187598.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30608896, 24027009]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 18602922, 30608896, 26318770]. This variant is expected to disrupt protein structure [Myriad internal data].

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

Last Updated: Nov 24, 2024

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