NM_000535.7(PMS2):c.2T>A (p.Met1Lys) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 6, 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:: RCV000212834.12

Allele description [Variation Report for NM_000535.7(PMS2):c.2T>A (p.Met1Lys)]

NM_000535.7(PMS2):c.2T>A (p.Met1Lys)

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.2T>A (p.Met1Lys)

Other names:

p.M1K:ATG>AAG

HGVS:

NC_000007.14:g.6009018A>T
NG_008466.1:g.5089T>A
NG_050738.1:g.4768A>T
NM_000535.7:c.2T>AMANE SELECT
NM_001322003.2:c.-399T>A
NM_001322004.2:c.-264T>A
NM_001322005.2:c.-594T>A
NM_001322006.2:c.2T>A
NM_001322007.2:c.-214T>A
NM_001322008.2:c.-74T>A
NM_001322009.2:c.-589T>A
NM_001322010.2:c.-264T>A
NM_001322011.2:c.-883T>A
NM_001322012.2:c.-878T>A
NM_001322013.2:c.-399T>A
NM_001322014.2:c.2T>A
NM_001322015.2:c.-478T>A
NP_000526.2:p.Met1Lys
NP_001308935.1:p.Met1Lys
NP_001308943.1:p.Met1Lys
LRG_161t1:c.2T>A
LRG_161:g.5089T>A
NC_000007.13:g.6048649A>T
NM_000535.5:c.2T>A
NM_000535.6:c.2T>A
NR_136154.1:n.89T>A
p.M1K

Protein change:

M1K

Links:

dbSNP: rs587780059

NCBI 1000 Genomes Browser:

rs587780059

Molecular consequence:

NM_001322003.2:c.-399T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322004.2:c.-264T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322005.2:c.-594T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322007.2:c.-214T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322008.2:c.-74T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322009.2:c.-589T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322010.2:c.-264T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322011.2:c.-883T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-878T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.-399T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322015.2:c.-478T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000535.7:c.2T>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001322006.2:c.2T>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001322014.2:c.2T>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000535.7:c.2T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.2T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.89T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211587	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 6, 2023)	germline	clinical testing	Citation Link,
SCV002774370	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jun 18, 2021)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 28466842, 27476653, 26681312, 30764633, 28514183, 25559809, 30787465, 31447099, 32719484, 33087929, 26467025
SCV003818401	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 20, 2022)	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

SCV000211587

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 6, 2023)

germline

clinical testing

Citation Link,

SCV002774370

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Jun 18, 2021)

unknown

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV003818401

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 20, 2022)

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

Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2.

Haraldsdottir S, Rafnar T, Frankel WL, Einarsdottir S, Sigurdsson A, Hampel H, Snaebjornsson P, Masson G, Weng D, Arngrimsson R, Kehr B, Yilmaz A, Haraldsson S, Sulem P, Stefansson T, Shields PG, Sigurdsson F, Bekaii-Saab T, Moller PH, Steinarsdottir M, Alexiusdottir K, Hitchins M, et al.

Nat Commun. 2017 May 3;8:14755. doi: 10.1038/ncomms14755.

PubMed [citation]

PMID:: 28466842
PMCID:: PMC5418568

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis.

Adam R, Spier I, Zhao B, Kloth M, Marquez J, Hinrichsen I, Kirfel J, Tafazzoli A, Horpaopan S, Uhlhaas S, Stienen D, Friedrichs N, Altmüller J, Laner A, Holzapfel S, Peters S, Kayser K, Thiele H, Holinski-Feder E, Marra G, Kristiansen G, Nöthen MM, et al.

Am J Hum Genet. 2016 Aug 4;99(2):337-51. doi: 10.1016/j.ajhg.2016.06.015. Epub 2016 Jul 28.

PubMed [citation]

PMID:: 27476653
PMCID:: PMC4974087

See all PubMed Citations (12)

Details of each submission

From GeneDx, SCV000211587.13

#	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; Described as a pathogenic founder variant in the Icelandic population (Haraldsdottir et al., 2017); Identified in the heterozygous state in an individual with a personal and family history of colorectal cancer (Chubb et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 27742654, 30787465, 31447099, 28466842, 25559809, 27476653, 29922827, 32719484, 33087929, 30764633)

#	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, SCV002774370.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This variant is located in the translation initiation codon of the PMS2 mRNA and is predicted to interfere with PMS2 protein synthesis. The variant has been reported in affected individuals with colorectal cancer in the published literature (PMIDs: 25559809 (2015) and 26681312 (2015)). This variant has also been reported in individuals with constitutional mismatch repair deficiency syndrome who also carried a second pathogenic PMS2 variant (PMIDs: 27476653 (2016) and 30764633 (2018)). 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 Revvity Omics, Revvity, SCV003818401.3

#	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: Jul 29, 2024

ClinVar

Relating variation to medicine