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NM_000535.7(PMS2):c.2192_2196del (p.Leu731fs) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Sep 18, 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:
RCV000163763.13

Allele description [Variation Report for NM_000535.7(PMS2):c.2192_2196del (p.Leu731fs)]

NM_000535.7(PMS2):c.2192_2196del (p.Leu731fs)

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.2192_2196del (p.Leu731fs)
HGVS:
  • NC_000007.13:g.6018306_6018310del
  • NC_000007.14:g.5978679_5978683del
  • NG_008466.1:g.35428_35432del
  • NM_000535.7:c.2192_2196delMANE SELECT
  • NM_001322003.2:c.1787_1791del
  • NM_001322004.2:c.1787_1791del
  • NM_001322005.2:c.1787_1791del
  • NM_001322006.2:c.2036_2040del
  • NM_001322007.2:c.1874_1878del
  • NM_001322008.2:c.1874_1878del
  • NM_001322009.2:c.1787_1791del
  • NM_001322010.2:c.1631_1635del
  • NM_001322011.2:c.1259_1263del
  • NM_001322012.2:c.1259_1263del
  • NM_001322013.2:c.1619_1623del
  • NM_001322014.2:c.2192_2196del
  • NM_001322015.2:c.1883_1887del
  • NP_000526.2:p.Leu731fs
  • NP_001308932.1:p.Leu596fs
  • NP_001308933.1:p.Leu596fs
  • NP_001308934.1:p.Leu596fs
  • NP_001308935.1:p.Leu679fs
  • NP_001308936.1:p.Leu625fs
  • NP_001308937.1:p.Leu625fs
  • NP_001308938.1:p.Leu596fs
  • NP_001308939.1:p.Leu544fs
  • NP_001308940.1:p.Leu420fs
  • NP_001308941.1:p.Leu420fs
  • NP_001308942.1:p.Leu540fs
  • NP_001308943.1:p.Leu731fs
  • NP_001308944.1:p.Leu628fs
  • LRG_161t1:c.2192_2196del
  • LRG_161:g.35428_35432del
  • NC_000007.13:g.6018306_6018310del
  • NC_000007.13:g.6018306_6018310delAGTTA
  • NC_000007.13:g.6018310_6018314del
  • NC_000007.14:g.5978675_5978679delAGTTA
  • NM_000535.5:c.2192_2196delTAACT
  • NM_000535.6:c.2192_2196del
  • NM_000535.7:c.2192_2196delTAACTMANE SELECT
  • NR_136154.1:n.2279_2283del
  • p.L731Cfs*3
  • p.Leu731CysfsX3
Protein change:
L420fs
Links:
dbSNP: rs63750695
NCBI 1000 Genomes Browser:
rs63750695
Molecular consequence:
  • NM_000535.7:c.2192_2196del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322003.2:c.1787_1791del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322004.2:c.1787_1791del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322005.2:c.1787_1791del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322006.2:c.2036_2040del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322007.2:c.1874_1878del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322008.2:c.1874_1878del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322009.2:c.1787_1791del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322010.2:c.1631_1635del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322011.2:c.1259_1263del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322012.2:c.1259_1263del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322013.2:c.1619_1623del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322014.2:c.2192_2196del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001322015.2:c.1883_1887del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NR_136154.1:n.2279_2283del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000214343Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Sep 18, 2024) 		germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link,

SCV004359033Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Sep 1, 2023) 		germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.

Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, Lindblom A, Lagerstedt K, Thibodeau SN, Lindor NM, Young J, Winship I, Dowty JG, White DM, Hopper JL, Baglietto L, Jenkins MA, de la Chapelle A.

Gastroenterology. 2008 Aug;135(2):419-28. doi: 10.1053/j.gastro.2008.04.026. Epub 2008 May 2.

PubMed [citation]
PMID:
18602922
PMCID:
PMC2759321

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 (15)

Details of each submission

From Ambry Genetics, SCV000214343.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

The c.2192_2196delTAACT pathogenic mutation, located in coding exon 13 of the PMS2 gene, results from a deletion of 5 nucleotides at nucleotide positions 2192 to 2196, causing a translational frameshift with a predicted alternate stop codon (p.L731Cfs*3). This mutation has been reported in several individuals diagnosed with early onset colon cancer whose tumors showed isolated loss of PMS2 by IHC and/or microsatellite instability (Nakagawa H et al. Cancer Res. 2004 Jul 15;64(14):4721-7; Hampel H et al. N. Engl. J. Med. 2005 May 5;352(18):1851-60; Senter L et al. Gastroenterology 2008 Aug;135(2):419-28; van Lier MG et al. J. Pathol. 2012 Apr;226:764-74; Lee J et al. Gynecol Oncol, 2018 10;151:153-158; Wang Q et al. J Med Genet, 2020 07;57:487-499). This mutation has also been reported in a patient with breast and ovarian cancer and a family history of breast and pancreatic cancer (Shirts BH et al. Genet. Med. 2016 10;18:974-81), as a germline mutation in an ovarian cancer patient with a microsatellite unstable tumor and family history of breast and/or ovarian cancer (Jorge S et al. Gynecol Oncol, 2020 03;156:517-522), and in 1/107 Macedonian individuals with a clinical history of hereditary polyposis or hereditary non-polyposis colorectal cancer who underwent multi-gene panel testing (Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16). Of note, this alteration is also designated as c.2192_2196del5 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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

From Color Diagnostics, LLC DBA Color Health, SCV004359033.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

This variant deletes 5 nucleotides in exon 13 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An RNA study suggests the unstable expression of the variant transcript (PMID: 20186688). This variant has been reported in at least 10 individuals affected with Lynch syndrome-associated cancers (PMID: 15256438, 15872200, 20186688, 22081473, 26845104, 27435373, 28874130, 30077346, 31942411, 31992580). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

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

Last Updated: Jan 13, 2025