NM_000535.7(PMS2):c.2521del (p.Trp841fs) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Pathogenic (Last evaluated: Jun 1, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000552542.4

Allele description [Variation Report for NM_000535.7(PMS2):c.2521del (p.Trp841fs)]

NM_000535.7(PMS2):c.2521del (p.Trp841fs)

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.2521del (p.Trp841fs)
HGVS:
  • NC_000007.14:g.5973467del
  • NG_008466.1:g.40640del
  • NM_000535.7:c.2521delMANE SELECT
  • NM_001322003.2:c.2116del
  • NM_001322004.2:c.2116del
  • NM_001322005.2:c.2116del
  • NM_001322006.2:c.2365del
  • NM_001322007.1:c.2203del
  • NM_001322008.2:c.2203del
  • NM_001322009.2:c.2149del
  • NM_001322010.2:c.1960del
  • NM_001322011.2:c.1588del
  • NM_001322012.2:c.1588del
  • NM_001322013.2:c.1948del
  • NM_001322014.2:c.2554del
  • NM_001322015.2:c.2212del
  • NP_000526.2:p.Trp841fs
  • NP_001308932.1:p.Trp706fs
  • NP_001308933.1:p.Trp706fs
  • NP_001308934.1:p.Trp706fs
  • NP_001308935.1:p.Trp789fs
  • NP_001308936.1:p.Trp735fs
  • NP_001308937.1:p.Trp735fs
  • NP_001308938.1:p.Trp717fs
  • NP_001308939.1:p.Trp654fs
  • NP_001308940.1:p.Trp530fs
  • NP_001308941.1:p.Trp530fs
  • NP_001308942.1:p.Trp650fs
  • NP_001308943.1:p.Trp852fs
  • NP_001308944.1:p.Trp738fs
  • LRG_161t1:c.2521del
  • LRG_161:g.40640del
  • NC_000007.13:g.6013098del
  • NM_000535.5:c.2521del
  • NM_000535.5:c.2521delT
  • NM_000535.6:c.2521del
  • NR_136154.1:n.2565del
  • p.Trp841fs
Protein change:
W530fs
Links:
dbSNP: rs886039646
NCBI 1000 Genomes Browser:
rs886039646
Molecular consequence:
  • NM_000535.7:c.2521del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322003.2:c.2116del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322004.2:c.2116del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322005.2:c.2116del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322006.2:c.2365del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322007.1:c.2203del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322008.2:c.2203del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322009.2:c.2149del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322010.2:c.1960del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322011.2:c.1588del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322012.2:c.1588del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322013.2:c.1948del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322014.2:c.2554del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322015.2:c.2212del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NR_136154.1:n.2565del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000625623Invitaecriteria provided, single submitter
Pathogenic
(Jun 1, 2020)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Effective Immunotherapy of Glioblastoma in an Adolescent with Constitutional Mismatch Repair-Deficiency Syndrome.

Pavelka Z, Zitterbart K, Nosková H, Bajčiová V, Slabý O, Štěrba J.

Klin Onkol. Winter 2019;32(1):70-74. doi: 10.14735/amko201970.

PubMed [citation]
PMID:
30764633

Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome.

Maletzki C, Huehns M, Bauer I, Ripperger T, Mork MM, Vilar E, Klöcking S, Zettl H, Prall F, Linnebacher M.

Mol Carcinog. 2017 Jul;56(7):1753-1764. doi: 10.1002/mc.22632. Epub 2017 Mar 30.

PubMed [citation]
PMID:
28218421
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000625623.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change results in a premature translational stop signal in the PMS2 gene (p.Trp841Glyfs*10). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acids of the PMS2 protein. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed to co-occur with a second pathogenic PMS2 variant (c.2T>A) in an individual with constitutional mismatch repair deficiency syndrome (CMMR-D) (PMID: 30764633), and an individual affected with glioblastoma multiforme (PMID: 28218421). ClinVar contains an entry for this variant (Variation ID: 265586). This variant has been reported to affect PMS2 protein function (PMID: 26116798). This variant is expected to remove the C-terminal portion of the MLH1 interaction domain (amino acids 675-850), which has been shown to be critical for PMS2-MLH1 dimerization (PMID: 10037723), and therefore mismatch repair activity (PMID: 16338176, 20533529). This suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 26, 2021

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