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NM_000251.3(MSH2):c.518T>C (p.Leu173Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jun 22, 2020
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:
RCV002336228.9

Allele description [Variation Report for NM_000251.3(MSH2):c.518T>C (p.Leu173Pro)]

NM_000251.3(MSH2):c.518T>C (p.Leu173Pro)

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.518T>C (p.Leu173Pro)
HGVS:
  • NC_000002.12:g.47410245T>C
  • NG_007110.2:g.12122T>C
  • NM_000251.3:c.518T>CMANE SELECT
  • NM_001258281.1:c.320T>C
  • NP_000242.1:p.Leu173Pro
  • NP_000242.1:p.Leu173Pro
  • NP_001245210.1:p.Leu107Pro
  • LRG_218t1:c.518T>C
  • LRG_218:g.12122T>C
  • LRG_218p1:p.Leu173Pro
  • NC_000002.11:g.47637384T>C
  • NM_000251.1:c.518T>C
  • NM_000251.2:c.518T>C
  • P43246:p.Leu173Pro
Protein change:
L107P
Links:
UniProtKB: P43246#VAR_043751; dbSNP: rs63750070
NCBI 1000 Genomes Browser:
rs63750070
Molecular consequence:
  • NM_000251.3:c.518T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258281.1:c.320T>C - 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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002643760Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Jun 22, 2020) 		germlineclinical testing

PubMed (10)
[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

Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.

Mangold E, Pagenstecher C, Friedl W, Mathiak M, Buettner R, Engel C, Loeffler M, Holinski-Feder E, Müller-Koch Y, Keller G, Schackert HK, Krüger S, Goecke T, Moeslein G, Kloor M, Gebert J, Kunstmann E, Schulmann K, Rüschoff J, Propping P.

Int J Cancer. 2005 Sep 20;116(5):692-702.

PubMed [citation]
PMID:
15849733

Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing.

Auclair J, Busine MP, Navarro C, Ruano E, Montmain G, Desseigne F, Saurin JC, Lasset C, Bonadona V, Giraud S, Puisieux A, Wang Q.

Hum Mutat. 2006 Feb;27(2):145-54.

PubMed [citation]
PMID:
16395668
See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV002643760.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

The p.L173P variant (also known as c.518T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 518. The leucine at codon 173 is replaced by proline, an amino acid with similar properties. This alteration was reported in an individual whose colorectal tumor demonstrated high microsatellite instabilty (MSI-H) with loss of MSH2 protein expression on immunohistochemistry (IHC) and had a family history that met Amsterdam criteria for Lynch syndrome (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17). This alteration was also identified as a somatic variant in conjunction with loss of heterozygosity of MSH2 in a Lynch syndrome-related tumor demonstrating MMR deficiency by IHC (Shirts BH et al. Am. J. Hum. Genet., 2018 07;103:19-29). In an in vitro complementation assay using human nuclear extracts from a colorectal cell line, this alteration demonstrated reduced (less than 10%) mismatch repair (MMR) activity compared to wild type MSH2 (Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17). In another functional study, this alteration showed resistance to a DNA damaging agent known to cause cell death in MMR-proficient cells, had reduced protein expression compared to wild type MSH2, and demonstrated microsatellite instability in a cellular assay using a slippage reporter (Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A., 2016 Apr;113:4128-33). Furthermore, this alteration demonstrated no aberrant splicing in a functional assay using RT-PCR (Auclair J et al. Hum. Mutat., 2006 Feb;27:145-54). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well 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 analysis (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