NM_000535.7(PMS2):c.1361T>C (p.Leu454Pro) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Feb 26, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [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 nonpolyposis colorectal neoplasms
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000552051Invitaecriteria provided, single submitter
Uncertain significance
(Feb 26, 2020)
germlineclinical testing

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

Summary from all submissions

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



Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

Details of each submission

From Invitae, SCV000552051.4

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


This sequence change replaces leucine with proline at codon 454 of the PMS2 protein (p.Leu454Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. The frequency data for this variant (rs772659239) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a PMS2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0). The proline amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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