NM_000535.7(PMS2):c.2T>A (p.Met1Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 31, 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:: RCV000160895.18

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:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000214325	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 16, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18602922, 23709753, 26681312, 27476653, 28466842 Citation Link,
SCV000691064	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25559809, 26681312, 27476653, 30764633, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000214325

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 16, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000691064

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 31, 2023)

germline

clinical testing

PubMed (5)
[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

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 (8)

Details of each submission

From Ambry Genetics, SCV000214325.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.M1? pathogenic mutation (also known as c.2T>A) is located in coding exon 1 of the PMS2 gene. This variant results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. This alteration was previously identified in a patient with colon cancer and in a patient with CMMRD who had another PMS2 mutation in trans (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32; Adam R et al. Am. J. Hum. Genet. 2016 Aug;99(2):337-51). Other alterations impacting the PMS2 initiation codon have been reported in individuals with early-onset, Lynch syndrome-associated malignancies and tumors demonstrating isolated loss of PMS2 staining by immunohistochemistry (IHC) (Senter et al. Gastroenterology. 2008 Aug;135(2):419-28; Borràs E et al. J. Med. Genet. 2013 Aug; 50(8):552-63). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000691064.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant results in the loss of the translation start codon of the PMS2 gene. Although functional studies have not been reported for this variant, it is expected to disrupt the expression of the full-length PMS2 protein. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809, 26681312) and in individuals affected with constitutional mismatch-repair deficiency who carried another pathogenic variant in PMS2 (PMID: 27476653, 30764633). This variant has been identified in 2/250260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different nucleotide substitutions affecting the same start codon are considered to be disease-causing (ClinVar variation ID: 91323, 127788, 142777, 231873, 957082, 450786, 820477), suggesting that this start codon is critical for PMS2 translation. Based on the available evidence, this variant is classified as 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: Jun 29, 2024

ClinVar

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