NM_000535.7(PMS2):c.2521del (p.Trp841fs) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Sep 11, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000255351.3

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)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000322576GeneDxcriteria provided, single submitter
Likely pathogenic
(Sep 11, 2017)
germlineclinical testing

Citation Link,

SCV000884400ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(Jul 27, 2017)
germlineclinical testing

Citation Link,

SCV001554334Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedLikely pathogenicunknownclinical testing

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000322576.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This deletion of one nucleotide in PMS2 is denoted c.2521delT at the cDNA level and p.Trp841GlyfsX10 (W841GfsX10) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCCC[delT]GGAA. The deletion causes a frameshift which changes a Tryptophan to a Glycine at codon 841, and creates a premature stop codon at position 10 of the new reading frame. Due to the position of the variant, nonsense-mediated decay is not expected to occur, but it might cause loss of normal protein function through protein truncation. The disrupted region at the end of the gene disrupts a zinc binding motif (Fukui 2011) and includes several residues which are conserved across species. PMS2 c.2521delT has been reported as either homozygous or with a second PMS2 variant in individuals suspected of having Constitutional Mismatch Repair Deficiency syndrome (Bodo 2015, Mach?ckov? 2016). Based on the currently available information, we consider this deletion to be a likely pathogenic variant.

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000884400.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The PMS2 c.2521delT;p.Trp841fs variant has been published at least once in an individual with suspected constitutional mismatch repair deficiency syndrome, who also carried an additional pathogenic PMS2 variant (Machackova 2016). However, it was not determined if these variants were on opposite chromosomes or if the reportedly healthy parents of this individual carried either variant. The c.2521delT;p.Trp841fs variant is listed in the ClinVar database (Variation ID: 265586), but not in the dbSNP variant database or in the general population-based databases (Genome Aggregation Database, Exome Variant Server). This variant deletes one nucleotide and causes a frameshift. However, this variant only truncates 22 amino acids of unclear function (Guerrette 1999, Kondo 2001). Considering available information, this variant cannot be classified with certainty. References: Guerrette S et al. The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. J Biol Chem. 1999 Mar 5;274(10):6336-41. Kondo E et al. The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2. Nucleic Acids Res. 2001 Apr 15;29(8):1695-702. Machackova E et al. Retrospective NGS Study in High-risk Hereditary Cancer Patients at Masaryk Memorial Cancer Institute. Klin Onkol. 2016;29 Suppl 1:S35-45.

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

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001554334.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The PMS2 p.Trp841Glyfs*10 variant was not identified in the literature however it was identified in dbSNP (ID: rs886039646) as “With Pathogenic allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: pathogenic by Ambry Genetics, likely pathogenic by GeneDx and Invitae and uncertain significance by Integrated Genetics/Laboratory Corporation of America), and Clinvitae (3x). The variant was not identified in COGR, Cosmic, Insight Colon Cancer Gene Variant Database, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2521del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 841 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to result in a truncated or absent protein however the variant is located at the C-term of the protein and it is unclear if this truncation would lead to nonsense mediated decay or loss of function. Notable there are no truncating variants 3’ of this variant listed as pathogenic in ClinVar. However studies have shown that the C-term of PMS2 is important for binding to MLH1 which is integral to PMS2 function (Kosinski 2010, Guerrette 1999). Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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

Last Updated: Jun 14, 2021

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