NM_000535.7(PMS2):c.163+5G>C AND Lynch syndrome 4

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 22, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002288300.3

Allele description [Variation Report for NM_000535.7(PMS2):c.163+5G>C]

NM_000535.7(PMS2):c.163+5G>C

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.163+5G>C

HGVS:

NC_000007.14:g.6005887C>G
NG_008466.1:g.8220G>C
NG_050738.1:g.1637C>G
NM_000535.7:c.163+5G>CMANE SELECT
NM_001322003.2:c.-243+5G>C
NM_001322004.2:c.-242-1829G>C
NM_001322005.2:c.-243+5G>C
NM_001322006.2:c.163+5G>C
NM_001322007.2:c.-53+5G>C
NM_001322008.2:c.-52-1829G>C
NM_001322009.2:c.-243+5G>C
NM_001322010.2:c.-242-1829G>C
NM_001322011.2:c.-722+5G>C
NM_001322012.2:c.-722+5G>C
NM_001322013.2:c.-243+5G>C
NM_001322014.2:c.163+5G>C
NM_001322015.2:c.-322+5G>C
LRG_161:g.8220G>C
NC_000007.13:g.6045518C>G

Molecular consequence:

NM_000535.7:c.163+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322003.2:c.-243+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322004.2:c.-242-1829G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322005.2:c.-243+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322006.2:c.163+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322007.2:c.-53+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322008.2:c.-52-1829G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322009.2:c.-243+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322010.2:c.-242-1829G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322011.2:c.-722+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322012.2:c.-722+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322013.2:c.-243+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322014.2:c.163+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322015.2:c.-322+5G>C - intron variant - [Sequence Ontology: SO:0001627]

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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C-terminal-binding protein 2 isoform X1 [Dermochelys coriacea]
C-terminal-binding protein 2 isoform X1 [Dermochelys coriacea]
gi|1950473180|ref|XP_038269836.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002579763	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004035270	Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen	no assertion criteria provided	Likely pathogenic	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002579763

MGZ Medical Genetics Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 22, 2021)

germline

clinical testing

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

SCV004035270

Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen

no assertion criteria provided

Likely pathogenic

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	4	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 MGZ Medical Genetics Center, SCV002579763.1

#	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 Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen, SCV004035270.1

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

Description

Colon carcinoma (and recurrent colon polyps), presence of multiple café-au-lait spots, and a striking family history of hereditary tumor predisposition

Description

The detected alteration is not reported in the dbSNP database (dbSNP151) yet. It is not yet listed in gnomAD (as of 09/14/2023). The variant affects a Cartegni consensus splice site. Splicing prediction programs predict an impact on splicing behavior for the variant (Splice Site Finder Like (SSF): -14.5% and MaxEntScan (MES): -59.2%). In the ClinVar database, the variant has been previously reported once (in the context of HNPCC) and is classified as a "variant of unclear clinical significance" (ClinVar ID: 1707370). To our knowledge, the variant has not been previously reported in the literature in association with CMMRD Based on current knowledge, the variant should be classified as a "likely pathogenic variant" based on the ACMG criteria. (14.09.2023)

#	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
2	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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