NM_000535.7(PMS2):c.736_741delinsTGTGTGTGAAG (p.Pro246_Pro247delinsCysValTer) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 1, 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:: RCV000235196.15

Allele description [Variation Report for NM_000535.7(PMS2):c.736_741delinsTGTGTGTGAAG (p.Pro246_Pro247delinsCysValTer)]

NM_000535.7(PMS2):c.736_741delinsTGTGTGTGAAG (p.Pro246_Pro247delinsCysValTer)

Gene:

PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.736_741delinsTGTGTGTGAAG (p.Pro246_Pro247delinsCysValTer)

Other names:

p.Pro246Cysfs*3

HGVS:

NC_000007.14:g.5997388_5997393delinsCTTCACACACA
NG_008466.1:g.16714_16719delinsTGTGTGTGAAG
NM_000535.7:c.736_741delinsTGTGTGTGAAGMANE SELECT
NM_001322003.2:c.331_336delinsTGTGTGTGAAG
NM_001322004.2:c.331_336delinsTGTGTGTGAAG
NM_001322005.2:c.331_336delinsTGTGTGTGAAG
NM_001322006.2:c.736_741delinsTGTGTGTGAAG
NM_001322007.2:c.418_423delinsTGTGTGTGAAG
NM_001322008.2:c.418_423delinsTGTGTGTGAAG
NM_001322009.2:c.331_336delinsTGTGTGTGAAG
NM_001322010.2:c.331_336delinsTGTGTGTGAAG
NM_001322011.2:c.-198_-193delinsTGTGTGTGAAG
NM_001322012.2:c.-198_-193delinsTGTGTGTGAAG
NM_001322013.2:c.163_168delinsTGTGTGTGAAG
NM_001322014.2:c.736_741delinsTGTGTGTGAAG
NM_001322015.2:c.427_432delinsTGTGTGTGAAG
NP_000526.2:p.Pro246_Pro247delinsCysValTer
NP_001308932.1:p.Pro111_Pro112delinsCysValTer
NP_001308933.1:p.Pro111_Pro112delinsCysValTer
NP_001308934.1:p.Pro111_Pro112delinsCysValTer
NP_001308935.1:p.Pro246_Pro247delinsCysValTer
NP_001308936.1:p.Pro140_Pro141delinsCysValTer
NP_001308937.1:p.Pro140_Pro141delinsCysValTer
NP_001308938.1:p.Pro111_Pro112delinsCysValTer
NP_001308939.1:p.Pro111_Pro112delinsCysValTer
NP_001308942.1:p.Pro55_Pro56delinsCysValTer
NP_001308943.1:p.Pro246_Pro247delinsCysValTer
NP_001308944.1:p.Pro143_Pro144delinsCysValTer
LRG_161t1:c.736_741delCCCCCTinsTGTGTGTGAAG
LRG_161:g.16714_16719delinsTGTGTGTGAAG
NC_000007.13:g.6037019_6037024delinsCTTCACACACA
NM_000535.5:c.736_741delCCCCCTinsTGTGTGTGAAG
NM_000535.6:c.736_741delCCCCCTinsTGTGTGTGAAG
NR_136154.1:n.823_828delinsTGTGTGTGAAG
p.P246CfsX3
p.Pro246CysfsX3

Links:

OMIM: 600259.0015; dbSNP: rs267608150

NCBI 1000 Genomes Browser:

rs267608150

Molecular consequence:

NM_001322011.2:c.-198_-193delinsTGTGTGTGAAG - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-198_-193delinsTGTGTGTGAAG - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NR_136154.1:n.823_828delinsTGTGTGTGAAG - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000535.7:c.736_741delinsTGTGTGTGAAG - nonsense - [Sequence Ontology: SO:0001587]
NM_001322003.2:c.331_336delinsTGTGTGTGAAG - nonsense - [Sequence Ontology: SO:0001587]
NM_001322004.2:c.331_336delinsTGTGTGTGAAG - nonsense - [Sequence Ontology: SO:0001587]
NM_001322005.2:c.331_336delinsTGTGTGTGAAG - nonsense - [Sequence Ontology: SO:0001587]
NM_001322006.2:c.736_741delinsTGTGTGTGAAG - nonsense - [Sequence Ontology: SO:0001587]
NM_001322007.2:c.418_423delinsTGTGTGTGAAG - nonsense - [Sequence Ontology: SO:0001587]
NM_001322008.2:c.418_423delinsTGTGTGTGAAG - nonsense - [Sequence Ontology: SO:0001587]
NM_001322009.2:c.331_336delinsTGTGTGTGAAG - nonsense - [Sequence Ontology: SO:0001587]
NM_001322010.2:c.331_336delinsTGTGTGTGAAG - nonsense - [Sequence Ontology: SO:0001587]
NM_001322013.2:c.163_168delinsTGTGTGTGAAG - nonsense - [Sequence Ontology: SO:0001587]
NM_001322014.2:c.736_741delinsTGTGTGTGAAG - nonsense - [Sequence Ontology: SO:0001587]
NM_001322015.2:c.427_432delinsTGTGTGTGAAG - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149612	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 11, 2020)	germline	clinical testing	Citation Link,
SCV001470606	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Apr 27, 2022)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 30702970, 28466842, 21376568, 18602922, 18178629, 27435373, 26467025
SCV002586166	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2023)	germline	clinical testing	Citation Link,
SCV004227262	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 27, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20186688, 21376568, 28466842, 32773772, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	5	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive Paired Tumor/Germline Testing for Lynch Syndrome: Bringing Resolution to the Diagnostic Process.

Salvador MU, Truelson MRF, Mason C, Souders B, LaDuca H, Dougall B, Black MH, Fulk K, Profato J, Gutierrez S, Jasperson K, Tippin-Davis B, Lu HM, Gray P, Shah S, Chao EC, Ghahramani N, Landsverk M, Gau CL, Chen D, Pronold M.

J Clin Oncol. 2019 Mar 10;37(8):647-657. doi: 10.1200/JCO.18.00696. Epub 2019 Jan 31.

PubMed [citation]

PMID:: 30702970
PMCID:: PMC6494248

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

See all PubMed Citations (10)

Details of each submission

From GeneDx, SCV000149612.13

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

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with Lynch syndrome (LS) and LS-related cancers as well as in individuals with constitutional mismatch repair deficiency (CMMR-D) syndrome (Clendenning 2008, Senter 2008, Herkert 2011, Alexander 2016, Rosty 2016, Wang 2020); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.736_741del6ins11; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 20205264, 22577899, 18602922, 30702970, 16619239, 24323032, 18178629, 21376568, 20487569, 20093870, 26552419, 25856668, 26895986, 27037742, 22081473, 26845104, 26681312, 27601186, 28418444, 29485237, 28466842, 23733757, 16817031, 21204794, 20682701, 29790872, 30322717, 31992580, 31447099, 33193653, 32719484, 32773772)

#	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, SCV001470606.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The PMS2 c.736_741delinsTGTGTGTGAAG (p.Pro246Cysfs*3) variant alters the translational reading frame of the PMS2 mRNA and causes the premature termination of PMS2 protein synthesis. This variant has been reported in the published literature in several individuals and families affected with a Lynch syndrome associated cancer and/or polyps (PMIDs: 18602922 (2008), 27435373 (2016), 28466842 (2017), 30702970 (2019)), as well as in an individual affected with CMMRD (PMID: 21376568 (2011)). 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 CeGaT Center for Human Genetics Tuebingen, SCV002586166.9

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

Description

PMS2: PVS1, PS4:Moderate

#	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		5	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV004227262.1

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

Description

PP4, PP5, PM2, PM3, PS4_moderate, PVS1

#	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		1	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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