NM_000535.7(PMS2):c.251-2A>T AND Lynch syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 22, 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:: RCV000205731.15

Allele description [Variation Report for NM_000535.7(PMS2):c.251-2A>T]

NM_000535.7(PMS2):c.251-2A>T

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.251-2A>T

HGVS:

NC_000007.14:g.6003794T>A
NG_008466.1:g.10313A>T
NM_000535.7:c.251-2A>TMANE SELECT
NM_001322003.2:c.-155-2A>T
NM_001322004.2:c.-155-2A>T
NM_001322005.2:c.-155-2A>T
NM_001322006.2:c.251-2A>T
NM_001322007.2:c.35+178A>T
NM_001322008.2:c.35+178A>T
NM_001322009.2:c.-155-2A>T
NM_001322010.2:c.-155-2A>T
NM_001322011.2:c.-634-2A>T
NM_001322012.2:c.-634-2A>T
NM_001322013.2:c.-155-2A>T
NM_001322014.2:c.251-2A>T
NM_001322015.2:c.-234-2A>T
NM_001406866.1:c.437-2A>T
NM_001406868.1:c.273A>T
NM_001406869.1:c.251-2A>T
NM_001406870.1:c.251-2A>T
NM_001406871.1:c.251-2A>T
NM_001406872.1:c.251-2A>T
NM_001406873.1:c.251-2A>T
NM_001406874.1:c.251-2A>T
NM_001406875.1:c.-234-2A>T
NM_001406876.1:c.35+178A>T
NM_001406877.1:c.-234-2A>T
NM_001406878.1:c.-234-2A>T
NM_001406879.1:c.-234-2A>T
NM_001406880.1:c.-181-2A>T
NM_001406881.1:c.-132+178A>T
NM_001406882.1:c.-234-2A>T
NM_001406883.1:c.35+178A>T
NM_001406884.1:c.251-2A>T
NM_001406885.1:c.250+178A>T
NM_001406886.1:c.251-2A>T
NM_001406887.1:c.-155-2A>T
NM_001406888.1:c.-102-2A>T
NM_001406889.1:c.-102-2A>T
NM_001406890.1:c.-145-2A>T
NM_001406891.1:c.-155-2A>T
NM_001406892.1:c.-102-2A>T
NM_001406893.1:c.-155-2A>T
NM_001406894.1:c.-102-2A>T
NM_001406895.1:c.-102-2A>T
NM_001406896.1:c.-52-1158A>T
NM_001406897.1:c.-155-2A>T
NM_001406898.1:c.-155-2A>T
NM_001406899.1:c.-102-2A>T
NM_001406900.1:c.-132+178A>T
NM_001406901.1:c.35+178A>T
NM_001406902.1:c.35+178A>T
NM_001406903.1:c.35+178A>T
NM_001406904.1:c.-102-2A>T
NM_001406905.1:c.-155-2A>T
NM_001406906.1:c.-155-2A>T
NM_001406907.1:c.-102-2A>T
NM_001406908.1:c.-155-2A>T
NM_001406909.1:c.-102-2A>T
NM_001406910.1:c.-155-2A>T
NM_001406911.1:c.-155-2A>T
NM_001406912.1:c.251-2A>T
NP_001393797.1:p.Ser91=
LRG_161t1:c.251-2A>T
LRG_161:g.10313A>T
NC_000007.13:g.6043425T>A
NM_000535.5:c.251-2A>T
NM_000535.6:c.251-2A>T

Links:

dbSNP: rs587779340

NCBI 1000 Genomes Browser:

rs587779340

Molecular consequence:

NM_001322007.2:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001322008.2:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001406876.1:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001406881.1:c.-132+178A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001406883.1:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001406885.1:c.250+178A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001406896.1:c.-52-1158A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001406900.1:c.-132+178A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001406901.1:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001406902.1:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001406903.1:c.35+178A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000535.7:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001322003.2:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001322004.2:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001322005.2:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001322006.2:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001322009.2:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001322010.2:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001322011.2:c.-634-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001322012.2:c.-634-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001322013.2:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001322014.2:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001322015.2:c.-234-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406866.1:c.437-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406869.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406870.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406871.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406872.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406873.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406874.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406875.1:c.-234-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406877.1:c.-234-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406878.1:c.-234-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406879.1:c.-234-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406880.1:c.-181-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406882.1:c.-234-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406884.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406886.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406887.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406888.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406889.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406890.1:c.-145-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406891.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406892.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406893.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406894.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406895.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406897.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406898.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406899.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406904.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406905.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406906.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406907.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406908.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406909.1:c.-102-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406910.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406911.1:c.-155-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406912.1:c.251-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406868.1:c.273A>T - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

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
SCV000266117	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Shirts et al. (Genet Med 2016))	Likely pathogenic (Nov 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000967786	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 9, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21376568, 18602922, 25980754, 24033266
SCV004814295	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25980754, 31992580, 33881185, 35982947, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000266117

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Shirts et al. (Genet Med 2016))

Likely pathogenic
(Nov 20, 2015)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000967786

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Mar 9, 2018)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004814295

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 22, 2024)

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	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Improving performance of multigene panels for genomic analysis of cancer predisposition.

Shirts BH, Casadei S, Jacobson AL, Lee MK, Gulsuner S, Bennett RL, Miller M, Hall SA, Hampel H, Hisama FM, Naylor LV, Goetsch C, Leppig K, Tait JF, Scroggins SM, Turner EH, Livingston R, Salipante SJ, King MC, Walsh T, Pritchard CC.

Genet Med. 2016 Oct;18(10):974-81. doi: 10.1038/gim.2015.212. Epub 2016 Feb 4.

PubMed [citation]

PMID:: 26845104

Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines.

Herkert JC, Niessen RC, Olderode-Berends MJ, Veenstra-Knol HE, Vos YJ, van der Klift HM, Scheenstra R, Tops CM, Karrenbeld A, Peters FT, Hofstra RM, Kleibeuker JH, Sijmons RH.

Eur J Cancer. 2011 May;47(7):965-82. doi: 10.1016/j.ejca.2011.01.013. Epub 2011 Mar 4. Review.

PubMed [citation]

PMID:: 21376568

See all PubMed Citations (9)

Details of each submission

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000266117.1

#	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	1	not provided	not provided		1	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967786.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The c.251-2A>T variant in PMS2 has been reported in one individual with suspecte d Lynch syndrome (Yurgelun 2015) and has also been reported by other clinical la boratories in ClinVar (Variation ID# 183893). Additionally, two other variants a t this position (c.251-2A>C, c.251A>G) have been reported in individuals with PM S2-related cancers (Herkert 2011, Senter 2008), one of which has also been class ified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108354.2). The c.251A>T variant has also been identified in 1/108456 European chromosomes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org; dbSNP rs587779340). This frequency is low enough to be consistent with the frequency of Lynch syndrome in the general population. T his variant occurs in the invariant region (+/- 1,2) of the splice consensus seq uence and is predicted to cause altered splicing leading to an abnormal or absen t protein. Heterozygous loss of function of the PMS2 gene is an established dise ase mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal domi nant manner based upon predicted impact to the protein, very low frequency in th e general population and the presence of a different pathogenic variant at the s ame position. ACMG/AMP criteria applied (Richards 2015): PVS1, PM5, PM2.

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

From All of Us Research Program, National Institutes of Health, SCV004814295.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (5)

Description

This variant causes an A to T nucleotide substitution at the -2 position of intron 3 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals suspected of having Lynch syndrome or colorectal cancer with clinical features of Lynch syndrome (PMID: 25980754, 31992580), in individuals with ovarian cancer (PMID: 33881185) and oligodendroglioma (PMID: 35982947). This variant has been identified in 1/244282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c..251-2A>G and c.251-2A>C, are known to be disease-causing (ClinVar variation ID: 91345, 233781). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). 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	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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