NM_000535.7(PMS2):c.2117del (p.Lys706fs) AND Lynch syndrome 4

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Feb 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:: RCV000709753.7

Allele description [Variation Report for NM_000535.7(PMS2):c.2117del (p.Lys706fs)]

NM_000535.7(PMS2):c.2117del (p.Lys706fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.2117del (p.Lys706fs)

HGVS:

NC_000007.13:g.6022512del
NC_000007.14:g.5982882del
NG_008466.1:g.31226del
NM_000535.7:c.2117delMANE SELECT
NM_001322003.2:c.1712del
NM_001322004.2:c.1712del
NM_001322005.2:c.1712del
NM_001322006.2:c.1961del
NM_001322007.2:c.1799del
NM_001322008.2:c.1799del
NM_001322009.2:c.1712del
NM_001322010.2:c.1556del
NM_001322011.2:c.1184del
NM_001322012.2:c.1184del
NM_001322013.2:c.1544del
NM_001322014.2:c.2117del
NM_001322015.2:c.1808del
NP_000526.2:p.Lys706fs
NP_001308932.1:p.Lys571fs
NP_001308933.1:p.Lys571fs
NP_001308934.1:p.Lys571fs
NP_001308935.1:p.Lys654fs
NP_001308936.1:p.Lys600fs
NP_001308937.1:p.Lys600fs
NP_001308938.1:p.Lys571fs
NP_001308939.1:p.Lys519fs
NP_001308940.1:p.Lys395fs
NP_001308941.1:p.Lys395fs
NP_001308942.1:p.Lys515fs
NP_001308943.1:p.Lys706fs
NP_001308944.1:p.Lys603fs
LRG_161t1:c.2117del
LRG_161:g.31226del
NC_000007.13:g.6022512del
NC_000007.13:g.6022512delT
NC_000007.13:g.6022513del
NC_000007.14:g.5982881delT
NM_000535.5:c.2117delA
NM_000535.6:c.2117delA
NM_000535.7:c.2117delAMANE SELECT
NR_136154.1:n.2204del
p.K706Sfs*19
p.Lys706SerfsX19
p.Lys706fs

Protein change:

K395fs

Links:

dbSNP: rs587782704

NCBI 1000 Genomes Browser:

rs587782704

Molecular consequence:

NM_000535.7:c.2117del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322003.2:c.1712del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322004.2:c.1712del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322005.2:c.1712del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322006.2:c.1961del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322007.2:c.1799del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322008.2:c.1799del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322009.2:c.1712del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322010.2:c.1556del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322011.2:c.1184del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322012.2:c.1184del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322013.2:c.1544del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322014.2:c.2117del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322015.2:c.1808del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_136154.1:n.2204del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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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carbonic anhydrase 13 [Homo sapiens]
carbonic anhydrase 13 [Homo sapiens]
gi|38348436|ref|NP_940986.1|

Protein
MIR5694 microRNA 5694 [Homo sapiens]
MIR5694 microRNA 5694 [Homo sapiens]
Gene ID:100847064

Gene
OGT [Macaca fascicularis]
OGT [Macaca fascicularis]
Gene ID:101866582

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000840045	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 19, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001434294	Division of Medical Genetics, University of Washington - CSER_CHARM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 6, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004171642	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	no assertion criteria provided	Pathogenic (Nov 24, 2023)	germline	clinical testing
SCV004187682	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Sep 21, 2023)	unknown	clinical testing	Citation Link,
SCV004207858	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 22, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000840045.1

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

Description

The c.2117delA (p.Lys706Serfs*19) variant has been in a 53 y/o female with colorectal cancer in the transverse colon [PMID 5856668], an also detected in a family with Lynch syndrome [PMID 26110232]. This variant was also recently detected at the homozygous state in 2 young siblings with recurrent gliobalstoma multiforme and NF1 features [PMID 27001570]. Treatment with the anti-programmed death-1 inhibitor nivolumab resulted in clinically significant responses and a profound radiologic response. This variant was not observed in the ExAC population database nor in our patient cohort. This 1 bp deletion is located in exon 12, and leads to a frameshift and a premature stop codon. This variant is expected to result in a loss of function of the protein and is thus classified as pathogenic. Pathogenic variant in the PMS2 gene are considered medically actionable [ACMG59, PMID 27854360]

#	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 Division of Medical Genetics, University of Washington - CSER_CHARM, SCV001434294.1

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

Description

This variant leads to a translational frameshift and the introduction of a premature termination codon 19 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of PMS2 is a well-established mechanism of disease for Lynch syndrome. This variant has been reported in the literature in an individual with colon cancer (Leiter 1965) and a family with Lynch syndrome (Suerink 2016). It has also been reported in individuals with constitutional mismatch repair deficiency syndrome (Bouffet 2016, Adam 2016). This variant is not present in population databases (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PM2; PVS1; PM3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Zotz-Klimas Genetics Lab, MVZ Zotz Klimas, SCV004171642.1

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

#	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 Myriad Genetics, Inc., SCV004187682.1

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

Description

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

#	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 Baylor Genetics, SCV004207858.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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