NM_000535.7(PMS2):c.1A>G (p.Met1Val) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Feb 6, 2024
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:: RCV000160894.21

Allele description [Variation Report for NM_000535.7(PMS2):c.1A>G (p.Met1Val)]

NM_000535.7(PMS2):c.1A>G (p.Met1Val)

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.1A>G (p.Met1Val)

Other names:

p.M1V:ATG>GTG

HGVS:

NC_000007.14:g.6009019T>C
NG_008466.1:g.5088A>G
NG_050738.1:g.4769T>C
NM_000535.7:c.1A>GMANE SELECT
NM_001322003.2:c.-400A>G
NM_001322004.2:c.-265A>G
NM_001322005.2:c.-595A>G
NM_001322006.2:c.1A>G
NM_001322007.2:c.-215A>G
NM_001322008.2:c.-75A>G
NM_001322009.2:c.-590A>G
NM_001322010.2:c.-265A>G
NM_001322011.2:c.-884A>G
NM_001322012.2:c.-879A>G
NM_001322013.2:c.-400A>G
NM_001322014.2:c.1A>G
NM_001322015.2:c.-479A>G
NP_000526.2:p.Met1Val
NP_001308935.1:p.Met1Val
NP_001308943.1:p.Met1Val
LRG_161t1:c.1A>G
LRG_161:g.5088A>G
NC_000007.13:g.6048650T>C
NM_000535.5:c.1A>G
NM_000535.6:c.1A>G
NR_136154.1:n.88A>G
c.1A>G
p.Met1?

Protein change:

M1V

Links:

dbSNP: rs587779333

NCBI 1000 Genomes Browser:

rs587779333

Molecular consequence:

NM_001322003.2:c.-400A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322004.2:c.-265A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322005.2:c.-595A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322007.2:c.-215A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322008.2:c.-75A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322009.2:c.-590A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322010.2:c.-265A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322011.2:c.-884A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-879A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.-400A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322015.2:c.-479A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000535.7:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001322006.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001322014.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000535.7:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.88A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211586	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 28, 2022)	germline	clinical testing	Citation Link,
SCV000601834	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Nov 23, 2022)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18602922, 23709753, 20487569, 23012243, 27064304, 26467025
SCV000885991	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Oct 20, 2017)	germline	clinical testing	Citation Link,
SCV002018876	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 4, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002760391	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 6, 2024)	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	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

Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants.

Borràs E, Pineda M, Cadiñanos J, Del Valle J, Brieger A, Hinrichsen I, Cabanillas R, Navarro M, Brunet J, Sanjuan X, Musulen E, van der Klift H, Lázaro C, Plotz G, Blanco I, Capellá G.

J Med Genet. 2013 Aug;50(8):552-63. doi: 10.1136/jmedgenet-2012-101511. Epub 2013 May 24.

PubMed [citation]

PMID:: 23709753

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000211586.18

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

Description

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Observed in patients in the heterozygous state with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Borras et al., 2013; Okkels et al., 2019; Tian et al., 2019; Wang et al., 2020); This variant is associated with the following publications: (PMID: 19283792, 25512458, 22577899, 32068069, 28466842, 31433215, 31447099, 21376568, 23709753, 20487569, 23012243, 21261604, 27064304, 28514183, 27476653, 26895986, 27435373, 26681312, 29485237, 28491141, 25980754, 31054147, 31491536, 31992580, 34308366, 30787465, 33087929, 18602922)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601834.4

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

Description

This variant disrupts the translation initiation codon of the PMS2 mRNA and is predicted to interfere with PMS2 protein synthesis. The frequency of this variant in the general population, 0.000023 (3/128208 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with colorectal cancer (PMID: 20487569 (2010)), endometrial cancer (PMID: 23709753 (2013)), and constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 18602922 (2008)). Based on the available information, this variant is classified as pathogenic.

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885991.2

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

#	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

From Revvity Omics, Revvity, SCV002018876.4

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002760391.4

#	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	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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