NM_000535.7(PMS2):c.988+4A>G AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Aug 19, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

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


PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • 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
dbSNP: rs763959308
NCBI 1000 Genomes Browser:
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]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000686264Color Health, Inccriteria provided, single submitter
Likely benign
(Apr 22, 2016)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001181266Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Aug 19, 2019)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

Details of each submission

From Color Health, Inc, SCV000686264.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Ambry Genetics, SCV001181266.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided


The c.988+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 9 in the PMS2 gene. This nucleotide position is well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to weaken the efficiency of the native splice donor site, but is not predicted to have a deleterious effect on this splice donor site by BDGP; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Nov 20, 2021

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