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NM_000251.3(MSH2):c.1865C>G (p.Pro622Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Feb 8, 2018
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000491622.4

Allele description [Variation Report for NM_000251.3(MSH2):c.1865C>G (p.Pro622Arg)]

NM_000251.3(MSH2):c.1865C>G (p.Pro622Arg)

Gene:
MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p21
Genomic location:
Preferred name:
NM_000251.3(MSH2):c.1865C>G (p.Pro622Arg)
HGVS:
  • NC_000002.12:g.47475130C>G
  • NG_007110.2:g.77007C>G
  • NM_000251.3:c.1865C>GMANE SELECT
  • NM_001258281.1:c.1667C>G
  • NP_000242.1:p.Pro622Arg
  • NP_000242.1:p.Pro622Arg
  • NP_001245210.1:p.Pro556Arg
  • LRG_218t1:c.1865C>G
  • LRG_218:g.77007C>G
  • LRG_218p1:p.Pro622Arg
  • NC_000002.11:g.47702269C>G
  • NM_000251.1:c.1865C>G
  • NM_000251.2:c.1865C>G
Protein change:
P556R
Links:
dbSNP: rs28929483
NCBI 1000 Genomes Browser:
rs28929483
Molecular consequence:
  • NM_000251.3:c.1865C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258281.1:c.1667C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000580538Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Feb 8, 2018) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

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

Citations

PubMed

Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study.

Jenkins MA, Baglietto L, Dowty JG, Van Vliet CM, Smith L, Mead LJ, Macrae FA, St John DJ, Jass JR, Giles GG, Hopper JL, Southey MC.

Clin Gastroenterol Hepatol. 2006 Apr;4(4):489-98.

PubMed [citation]
PMID:
16616355

Functional characterization of pathogenic human MSH2 missense mutations in Saccharomyces cerevisiae.

Gammie AE, Erdeniz N, Beaver J, Devlin B, Nanji A, Rose MD.

Genetics. 2007 Oct;177(2):707-21. Epub 2007 Aug 24.

PubMed [citation]
PMID:
17720936
PMCID:
PMC2034637
See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000580538.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

The p.P622R variant (also known as c.1865C>G), located in coding exon 12 of the MSH2 gene, results from a C to G substitution at nucleotide position 1865. The proline at codon 622 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in an individual with clinical features of Lynch syndrome (Ambry internal data). This alteration was also identified as somatic in an endometrial tumor that displayed high microsatellite instability (MSI-H) with loss of MSH2 as well as MSH6 on immunohistochemistry (IHC) and a germline likely pathogenic variant in MSH2 was determined to be in trans (Ambry internal data). A pathogenic mutation (p.P622L) at the same codon has been reported to segregate with disease in families that met Amsterdam I/II criteria for Lynch syndrome and results from tumor testing for these individuals showed absent MSH2/MSH6 on IHC and/or MSI-H (Leach FS et al. Cell 1993 Dec;75:1215-25; Van de Water NS et al. Aust. N Z J Med. 1994 Dec;24:682-6; Jenkins MA et al. Int. J. Cancer 2002 Nov;102:166-71; Southey MC et al. J. Clin. Oncol. 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98; Arnold S et al. Hum. Mutat., 2009 May;30:757-70). Also, numerous studies in mammalian and yeast systems have demonstrated that p.P622L results in reduced mismatch repair activity (Gammie AE et al. Genetics 2007 Oct;177:707-21; Lützen A et al. Mutat. Res. 2008 Oct;645:44-55; Mastrocola AS et al. Hum. Mutat. 2010 Oct;31:E1699-708; Wielders EA et al. Hum. Mutat. 2011 Apr;32:389-96; Drost M et al. Hum. Mutat. 2012 Mar;33:488-94; Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113:4128-33). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Nov 10, 2024