NM_000535.7(PMS2):c.214_215insAAGTTTCA (p.Gly72fs) AND Lynch syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 9, 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:: RCV004004942.3

Allele description [Variation Report for NM_000535.7(PMS2):c.214_215insAAGTTTCA (p.Gly72fs)]

NM_000535.7(PMS2):c.214_215insAAGTTTCA (p.Gly72fs)

Gene:

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

Variant type:

Insertion

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.214_215insAAGTTTCA (p.Gly72fs)

HGVS:

NC_000007.14:g.6004007_6004008insTGAAACTT
NG_008466.1:g.10099_10100insAAGTTTCA
NM_000535.7:c.214_215insAAGTTTCAMANE SELECT
NM_001322003.2:c.-192_-191insAAGTTTCA
NM_001322004.2:c.-192_-191insAAGTTTCA
NM_001322005.2:c.-192_-191insAAGTTTCA
NM_001322006.2:c.214_215insAAGTTTCA
NM_001322007.2:c.-2_-1insAAGTTTCA
NM_001322008.2:c.-2_-1insAAGTTTCA
NM_001322009.2:c.-192_-191insAAGTTTCA
NM_001322010.2:c.-192_-191insAAGTTTCA
NM_001322011.2:c.-671_-670insAAGTTTCA
NM_001322012.2:c.-671_-670insAAGTTTCA
NM_001322013.2:c.-192_-191insAAGTTTCA
NM_001322014.2:c.214_215insAAGTTTCA
NM_001322015.2:c.-271_-270insAAGTTTCA
NP_000526.2:p.Gly72fs
NP_001308935.1:p.Gly72fs
NP_001308943.1:p.Gly72fs
LRG_161t1:c.214_215insAAGTTTCA
LRG_161:g.10099_10100insAAGTTTCA
NC_000007.13:g.6043638_6043639insTGAAACTT
NM_000535.5:c.214_215insAAGTTTCA
NM_000535.6:c.214_215insAAGTTTCA
NR_136154.1:n.301_302insAAGTTTCA

Protein change:

G72fs

Links:

dbSNP: rs1785419483

NCBI 1000 Genomes Browser:

rs1785419483

Molecular consequence:

NM_001322003.2:c.-192_-191insAAGTTTCA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322004.2:c.-192_-191insAAGTTTCA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322005.2:c.-192_-191insAAGTTTCA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322007.2:c.-2_-1insAAGTTTCA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322008.2:c.-2_-1insAAGTTTCA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322009.2:c.-192_-191insAAGTTTCA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322010.2:c.-192_-191insAAGTTTCA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322011.2:c.-671_-670insAAGTTTCA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-671_-670insAAGTTTCA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.-192_-191insAAGTTTCA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322015.2:c.-271_-270insAAGTTTCA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000535.7:c.214_215insAAGTTTCA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322006.2:c.214_215insAAGTTTCA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322014.2:c.214_215insAAGTTTCA - frameshift variant - [Sequence Ontology: SO:0001589]
NR_136154.1:n.301_302insAAGTTTCA - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV004838931	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25512458, 28514183, 35223509, 25741868
SCV005045770	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 5, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004838931

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Jan 9, 2024)

germline

clinical testing

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

SCV005045770

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 5, 2023)

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

Citations

PubMed

Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk.

ten Broeke SW, Brohet RM, Tops CM, van der Klift HM, Velthuizen ME, Bernstein I, Capellá Munar G, Gomez Garcia E, Hoogerbrugge N, Letteboer TG, Menko FH, Lindblom A, Mensenkamp AR, Moller P, van Os TA, Rahner N, Redeker BJ, Sijmons RH, Spruijt L, Suerink M, Vos YJ, Wagner A, et al.

J Clin Oncol. 2015 Feb 1;33(4):319-25. doi: 10.1200/JCO.2014.57.8088. Epub 2014 Dec 15.

PubMed [citation]

PMID:: 25512458

Multigene Panel Testing Provides a New Perspective on Lynch Syndrome.

Espenschied CR, LaDuca H, Li S, McFarland R, Gau CL, Hampel H.

J Clin Oncol. 2017 Aug 1;35(22):2568-2575. doi: 10.1200/JCO.2016.71.9260. Epub 2017 May 17.

PubMed [citation]

PMID:: 28514183
PMCID:: PMC7186580

See all PubMed Citations (4)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004838931.1

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

Description

The c.214_215insAAGTTTCA variant is located in exon 3 of the PMS2 gene. This 8 bp insertion results in a shift of reading frame such that it introduces a premature translation termination codon (p.Gly72Glufs*7). It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 28514183, 25512458, 35223509). ClinVar contains an entry for this variant (ID: 993143). This variant is absent in the general population database (gnomAD). Therefore, the c.214_215insAAGTTTCA (p.Gly72Glufs*7) variant in the PMS2 gene is classified as likely 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		1	not provided	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV005045770.1

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

Description

#	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: Jun 2, 2024

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