NM_000535.7(PMS2):c.988+4A>G AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Nov 2, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000555625.6

Allele description [Variation Report for NM_000535.7(PMS2):c.988+4A>G]

NM_000535.7(PMS2):c.988+4A>G

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.988+4A>G
HGVS:
  • NC_000007.14:g.5991969T>C
  • NG_008466.1:g.22138A>G
  • NM_000535.7:c.988+4A>GMANE SELECT
  • NM_001322003.2:c.583+4A>G
  • NM_001322004.2:c.583+4A>G
  • NM_001322005.2:c.583+4A>G
  • NM_001322006.2:c.988+4A>G
  • NM_001322007.2:c.670+4A>G
  • NM_001322008.2:c.670+4A>G
  • NM_001322009.2:c.583+4A>G
  • NM_001322010.2:c.583+4A>G
  • NM_001322011.2:c.55+4A>G
  • NM_001322012.2:c.55+4A>G
  • NM_001322013.2:c.415+4A>G
  • NM_001322014.2:c.988+4A>G
  • NM_001322015.2:c.679+4A>G
  • LRG_161t1:c.988+4A>G
  • LRG_161:g.22138A>G
  • NC_000007.13:g.6031600T>C
  • NM_000535.5:c.988+4A>G
Links:
dbSNP: rs763959308
NCBI 1000 Genomes Browser:
rs763959308
Molecular consequence:
  • NM_000535.7:c.988+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322003.2:c.583+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322004.2:c.583+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322005.2:c.583+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322006.2:c.988+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322007.2:c.670+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322008.2:c.670+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322009.2:c.583+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322010.2:c.583+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322011.2:c.55+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322012.2:c.55+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322013.2:c.415+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322014.2:c.988+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322015.2:c.679+4A>G - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000625712Invitaecriteria provided, single submitter
Uncertain significance
(Nov 2, 2020)
germlineclinical testing

PubMed (3)
[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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]
PMID:
9536098
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000625712.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change falls in intron 9 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein, but it affects a nucleotide within the consensus splice site of the intron. While this variant is present in population databases (rs763959308), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 385124). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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