NM_000535.7(PMS2):c.1733G>A (p.Arg578His) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Mar 17, 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.1733G>A (p.Arg578His)]

NM_000535.7(PMS2):c.1733G>A (p.Arg578His)

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.1733G>A (p.Arg578His)
  • NC_000007.14:g.5987032C>T
  • NG_008466.1:g.27075G>A
  • NM_000535.7:c.1733G>AMANE SELECT
  • NM_001322003.2:c.1328G>A
  • NM_001322004.2:c.1328G>A
  • NM_001322005.2:c.1328G>A
  • NM_001322006.2:c.1577G>A
  • NM_001322007.2:c.1415G>A
  • NM_001322008.2:c.1415G>A
  • NM_001322009.2:c.1328G>A
  • NM_001322010.2:c.1172G>A
  • NM_001322011.2:c.800G>A
  • NM_001322012.2:c.800G>A
  • NM_001322013.2:c.1160G>A
  • NM_001322014.2:c.1733G>A
  • NM_001322015.2:c.1424G>A
  • NP_000526.2:p.Arg578His
  • NP_001308932.1:p.Arg443His
  • NP_001308933.1:p.Arg443His
  • NP_001308934.1:p.Arg443His
  • NP_001308935.1:p.Arg526His
  • NP_001308936.1:p.Arg472His
  • NP_001308937.1:p.Arg472His
  • NP_001308938.1:p.Arg443His
  • NP_001308939.1:p.Arg391His
  • NP_001308940.1:p.Arg267His
  • NP_001308941.1:p.Arg267His
  • NP_001308942.1:p.Arg387His
  • NP_001308943.1:p.Arg578His
  • NP_001308944.1:p.Arg475His
  • LRG_161t1:c.1733G>A
  • LRG_161:g.27075G>A
  • NC_000007.13:g.6026663C>T
  • NM_000535.5:c.1733G>A
  • NM_000535.6:c.1733G>A
  • NR_136154.1:n.1820G>A
Protein change:
dbSNP: rs63750770
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000535.7:c.1733G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322003.2:c.1328G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322004.2:c.1328G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322005.2:c.1328G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322006.2:c.1577G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322007.2:c.1415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322008.2:c.1415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322009.2:c.1328G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322010.2:c.1172G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322011.2:c.800G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322012.2:c.800G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322013.2:c.1160G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322014.2:c.1733G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322015.2:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_136154.1:n.1820G>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)
SCV000274787Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Feb 5, 2019)
germlineclinical testing

Citation Link,

SCV000686160Color Health, Inccriteria provided, single submitter
Likely benign
(Mar 17, 2020)
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



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, SCV000274787.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided


The p.R578H variant (also known as c.1733G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1733. The arginine at codon 578 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in a breast cancer patient who underwent a 25 gene multi-gene panel test (Tung N et al. Cancer. 2015 Jan 1;121(1):25-33). Although one study looking at the effect of nuclear localization signals on nuclear import demonstrated that a missense mutation at residue R578 reduced nuclear localization, a subsequent study demonstrated no effect (Brieger A et al. Mol Carcinog. 2005 May;43(1):51-8; Leong V et al. Mol Carcinog. 2009 Aug;48(8):742-50). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

From Color Health, Inc, SCV000686160.3

#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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