NM_000535.7(PMS2):c.1361T>C (p.Leu454Pro) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Jan 7, 2020)

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.1361T>C (p.Leu454Pro)]

NM_000535.7(PMS2):c.1361T>C (p.Leu454Pro)

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.1361T>C (p.Leu454Pro)
  • NC_000007.14:g.5987404A>G
  • NG_008466.1:g.26703T>C
  • NM_000535.7:c.1361T>CMANE SELECT
  • NM_001322003.2:c.956T>C
  • NM_001322004.2:c.956T>C
  • NM_001322005.2:c.956T>C
  • NM_001322006.2:c.1205T>C
  • NM_001322007.2:c.1043T>C
  • NM_001322008.2:c.1043T>C
  • NM_001322009.2:c.956T>C
  • NM_001322010.2:c.800T>C
  • NM_001322011.2:c.428T>C
  • NM_001322012.2:c.428T>C
  • NM_001322013.2:c.788T>C
  • NM_001322014.2:c.1361T>C
  • NM_001322015.2:c.1052T>C
  • NP_000526.2:p.Leu454Pro
  • NP_001308932.1:p.Leu319Pro
  • NP_001308933.1:p.Leu319Pro
  • NP_001308934.1:p.Leu319Pro
  • NP_001308935.1:p.Leu402Pro
  • NP_001308936.1:p.Leu348Pro
  • NP_001308937.1:p.Leu348Pro
  • NP_001308938.1:p.Leu319Pro
  • NP_001308939.1:p.Leu267Pro
  • NP_001308940.1:p.Leu143Pro
  • NP_001308941.1:p.Leu143Pro
  • NP_001308942.1:p.Leu263Pro
  • NP_001308943.1:p.Leu454Pro
  • NP_001308944.1:p.Leu351Pro
  • LRG_161t1:c.1361T>C
  • LRG_161:g.26703T>C
  • NC_000007.13:g.6027035A>G
  • NM_000535.5:c.1361T>C
  • NM_000535.6:c.1361T>C
  • NR_136154.1:n.1448T>C
Protein change:
dbSNP: rs772659239
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000535.7:c.1361T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322003.2:c.956T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322004.2:c.956T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322005.2:c.956T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322006.2:c.1205T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322007.2:c.1043T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322008.2:c.1043T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322009.2:c.956T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322010.2:c.800T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322011.2:c.428T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322012.2:c.428T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322013.2:c.788T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322014.2:c.1361T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322015.2:c.1052T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_136154.1:n.1448T>C - 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)
SCV000663428Ambry Geneticscriteria provided, single submitter
Likely benign
(Apr 23, 2018)
germlineclinical testing

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

Citation Link,

SCV001353133Color Health, Inccriteria provided, single submitter
Uncertain significance
(Jan 7, 2020)
germlineclinical testing

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


This missense variant replaces leucine with proline at codon 454 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251488 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.


Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation.

Borras E, Chang K, Pande M, Cuddy A, Bosch JL, Bannon SA, Mork ME, Rodriguez-Bigas MA, Taggart MW, Lynch PM, You YN, Vilar E.

Cancer Prev Res (Phila). 2017 Oct;10(10):580-587. doi: 10.1158/1940-6207.CAPR-17-0058. Epub 2017 Aug 1.

PubMed [citation]

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 Ambry Genetics, SCV000663428.3

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


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

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

From Color Health, Inc, SCV001353133.1

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

Last Updated: Oct 30, 2021

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