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NM_000251.3(MSH2):c.674C>G (p.Thr225Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 13, 2024
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:
RCV000563305.3

Allele description [Variation Report for NM_000251.3(MSH2):c.674C>G (p.Thr225Arg)]

NM_000251.3(MSH2):c.674C>G (p.Thr225Arg)

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.674C>G (p.Thr225Arg)
HGVS:
  • NC_000002.12:g.47412442C>G
  • NG_007110.2:g.14319C>G
  • NM_000251.3:c.674C>GMANE SELECT
  • NM_001258281.1:c.476C>G
  • NP_000242.1:p.Thr225Arg
  • NP_000242.1:p.Thr225Arg
  • NP_001245210.1:p.Thr159Arg
  • LRG_218t1:c.674C>G
  • LRG_218:g.14319C>G
  • LRG_218p1:p.Thr225Arg
  • NC_000002.11:g.47639581C>G
  • NM_000251.1:c.674C>G
  • NM_000251.2:c.674C>G
Protein change:
T159R
Links:
dbSNP: rs1553351576
NCBI 1000 Genomes Browser:
rs1553351576
Molecular consequence:
  • NM_000251.3:c.674C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258281.1:c.476C>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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000669772Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Mar 13, 2024) 		germlineclinical testing

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

Citation Link

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Summary from all submissions

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

Citations

PubMed

Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.

Jia X, Burugula BB, Chen V, Lemons RM, Jayakody S, Maksutova M, Kitzman JO.

Am J Hum Genet. 2021 Jan 7;108(1):163-175. doi: 10.1016/j.ajhg.2020.12.003. Epub 2020 Dec 23.

PubMed [citation]
PMID:
33357406
PMCID:
PMC7820803

Details of each submission

From Ambry Genetics, SCV000669772.5

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

Description

The p.T225R variant (also known as c.674C>G), located in coding exon 4 of the MSH2 gene, results from a C to G substitution at nucleotide position 674. The threonine at codon 225 is replaced by arginine, an amino acid with similar properties. This variant has been detected as homozygous in an individual with no reported features of MSH2-related constitutional mismatch repair deficiency (CMMRD) (Ambry internal data). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.

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

Last Updated: Sep 29, 2024