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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 14, 2019
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:: RCV004017444.1

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)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004848312	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 14, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27476653, 25559809, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004848312

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 14, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

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

Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing.

Chubb D, Broderick P, Frampton M, Kinnersley B, Sherborne A, Penegar S, Lloyd A, Ma YP, Dobbins SE, Houlston RS.

J Clin Oncol. 2015 Feb 10;33(5):426-32. doi: 10.1200/JCO.2014.56.5689. Epub 2015 Jan 5.

PubMed [citation]

PMID:: 25559809

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848312.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.Met? (c.2T>A) variant in PMS2 has been previously reported in 1 individual with rectal cancer in the heterozygous state (Chubb 2015) and 1 individual with constitutive mismatch repair deficiency in the compound heterozygous state (Adam 2016). It has been identified in 2/112800 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 182809), and classified as pathogenic by several clinical labs. This variant affects the translation initiation start codon (ATG) and is, therefore, predicted to disrupt translation. However, this exon is not present on all PMS2 transcripts. Therefore, the precise effect on the protein cannot be predicted, as this variant may lead to no protein synthesis or the activation of a downstream translation initiation codon, resulting in an alternative isoform. Other variants affecting this initiation codon have been reported in individuals with colorectal cancer and have been reported in ClinVar. In summary, the c.2T>A variant meets criteria to be classified as pathogenic for Lynch syndrome. ACMG/AMP Criteria applied: PVS1_Moderate, PS1, PM2, PM3.

#	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: Aug 11, 2024

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