NM_000535.7(PMS2):c.2T>A (p.Met1Lys) AND Lynch syndrome 4

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Apr 4, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000500749.19

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]

Observations:

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
SCV000596477	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 29, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000785677	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Pathogenic (Oct 27, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26681312, 25559809 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV001429095	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 16, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002579149	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 11, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004019807	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Apr 4, 2023)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30680046, 27476653, 18602922 Citation Link,
SCV004022255	deCODE genetics, Amgen	no assertion criteria provided	Pathogenic (Jul 21, 2023)	germline	research

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	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
Icelandic	germline	yes	144	not provided	not provided	not provided	not provided	research

Citations

PubMed

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, Vaccari EM, Bissonnette J, Booker JK, Cremona ML, Gibellini F, Murphy PD, Pineda-Alvarez DE, Pollevick GD, Xu Z, Richard G, Bale S, Klein RT, Hruska KS, Chung WK.

Genet Med. 2016 Aug;18(8):823-32. doi: 10.1038/gim.2015.166. Epub 2015 Dec 17. Erratum in: Genet Med. 2016 May;18(5):531-2. doi: 10.1038/gim.2016.21.

PubMed [citation]

PMID:: 26681312
PMCID:: PMC4985612

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 (6)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000596477.2

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000785677.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV001429095.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002579149.2

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

From Myriad Genetics, Inc., SCV004019807.2

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

Description

This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30680046, 27476653, 18602922].

#	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 deCODE genetics, Amgen, SCV004022255.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Icelandic	144	not provided	not provided	research	not provided

Description

The variant NM_000535.7:c.2T>A (chr7:6009018) in PMS2 was detected in 51 heterozygotes out of 58K WGS Icelanders (MAF= 0,044%). Following imputation in a set of 166K Icelanders (144 imputed heterozygotes) we observed an association with colorectal cancer using 4991 cases and 314812 controls (OR= 2.25, P= 4.86e-02). This variant has been reported in ClinVar previously as pathogenic and as a variant of uncertain significance. Based on ACMG criteria (PVS1, PS4) this variant classifies as pathogenic.

#	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		144	not provided	not provided	not provided

Last Updated: Jul 29, 2024

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