NM_000535.7(PMS2):c.433C>A (p.Gln145Lys) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Jan 27, 2021)

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.433C>A (p.Gln145Lys)]

NM_000535.7(PMS2):c.433C>A (p.Gln145Lys)

PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000535.7(PMS2):c.433C>A (p.Gln145Lys)
  • NC_000007.14:g.6002557G>T
  • NG_008466.1:g.11550C>A
  • NM_000535.7:c.433C>AMANE SELECT
  • NM_001322003.2:c.28C>A
  • NM_001322004.2:c.28C>A
  • NM_001322005.2:c.28C>A
  • NM_001322006.2:c.433C>A
  • NM_001322007.2:c.115C>A
  • NM_001322008.2:c.115C>A
  • NM_001322009.2:c.28C>A
  • NM_001322010.2:c.28C>A
  • NM_001322011.2:c.-452C>A
  • NM_001322012.2:c.-452C>A
  • NM_001322013.2:c.28C>A
  • NM_001322014.2:c.433C>A
  • NM_001322015.2:c.124C>A
  • NP_000526.2:p.Gln145Lys
  • NP_001308932.1:p.Gln10Lys
  • NP_001308933.1:p.Gln10Lys
  • NP_001308934.1:p.Gln10Lys
  • NP_001308935.1:p.Gln145Lys
  • NP_001308936.1:p.Gln39Lys
  • NP_001308937.1:p.Gln39Lys
  • NP_001308938.1:p.Gln10Lys
  • NP_001308939.1:p.Gln10Lys
  • NP_001308942.1:p.Gln10Lys
  • NP_001308943.1:p.Gln145Lys
  • NP_001308944.1:p.Gln42Lys
  • LRG_161t1:c.433C>A
  • LRG_161:g.11550C>A
  • NC_000007.13:g.6042188G>T
  • NM_000535.5:c.433C>A
  • NM_000535.6:c.433C>A
  • NR_136154.1:n.520C>A
Protein change:
dbSNP: rs786204133
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001322011.2:c.-452C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322012.2:c.-452C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000535.7:c.433C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322003.2:c.28C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322004.2:c.28C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322005.2:c.28C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322006.2:c.433C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322007.2:c.115C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322008.2:c.115C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322009.2:c.28C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322010.2:c.28C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322013.2:c.28C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322014.2:c.433C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322015.2:c.124C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_136154.1:n.520C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]


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)
SCV000275555Ambry Geneticscriteria provided, single submitter
Likely benign
(Feb 7, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000691075Color Health, Inccriteria provided, single submitter
Uncertain significance
(Jan 27, 2021)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.

Thompson BA, Greenblatt MS, Vallee MP, Herkert JC, Tessereau C, Young EL, Adzhubey IA, Li B, Bell R, Feng B, Mooney SD, Radivojac P, Sunyaev SR, Frebourg T, Hofstra RM, Sijmons RH, Boucher K, Thomas A, Goldgar DE, Spurdle AB, Tavtigian SV.

Hum Mutat. 2013 Jan;34(1):255-65. doi: 10.1002/humu.22214. Epub 2012 Oct 22.

PubMed [citation]

Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity.

Li S, Qian D, Thompson BA, Gutierrez S, Wu S, Pesaran T, LaDuca H, Lu HM, Chao EC, Black MH.

J Med Genet. 2020 Jan;57(1):62-69. doi: 10.1136/jmedgenet-2019-106096. Epub 2019 Aug 7.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000275555.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)


In silico models in agreement (benign);Other data supporting benign classification

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

From Color Health, Inc, SCV000691075.4

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


This missense variant replaces glutamine with lysine at codon 145 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in an individual affected with a Lynch syndrome-associated cancer (PMID: 31391288). This variant has been identified in 1/31404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

Last Updated: Dec 4, 2021

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