NM_000251.3(MSH2):c.1270C>T (p.His424Tyr) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Apr 25, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000464371.3

Allele description [Variation Report for NM_000251.3(MSH2):c.1270C>T (p.His424Tyr)]

NM_000251.3(MSH2):c.1270C>T (p.His424Tyr)

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.1270C>T (p.His424Tyr)
HGVS:
  • NC_000002.12:g.47429935C>T
  • NG_007110.2:g.31812C>T
  • NM_000251.2:c.1270C>T
  • NM_000251.3:c.1270C>TMANE SELECT
  • NM_001258281.1:c.1072C>T
  • NP_000242.1:p.His424Tyr
  • NP_000242.1:p.His424Tyr
  • NP_001245210.1:p.His358Tyr
  • LRG_218t1:c.1270C>T
  • LRG_218:g.31812C>T
  • LRG_218p1:p.His424Tyr
  • NC_000002.11:g.47657074C>T
  • NM_000251.1:c.1270C>T
  • p.H424Y
Protein change:
H358Y
Links:
dbSNP: rs587782278
NCBI 1000 Genomes Browser:
rs587782278
Molecular consequence:
  • NM_000251.2:c.1270C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000251.3:c.1270C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258281.1:c.1072C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000548214Invitaecriteria provided, single submitter
Uncertain significance
(Apr 25, 2019)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.

Pal T, Akbari MR, Sun P, Lee JH, Fulp J, Thompson Z, Coppola D, Nicosia S, Sellers TA, McLaughlin J, Risch HA, Rosen B, Shaw P, Schildkraut J, Narod SA.

Br J Cancer. 2012 Nov 6;107(10):1783-90. doi: 10.1038/bjc.2012.452. Epub 2012 Oct 9.

PubMed [citation]
PMID:
23047549
PMCID:
PMC3493867

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]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000548214.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces histidine with tyrosine at codon 424 of the MSH2 protein (p.His424Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant was reported in an individual affected with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 142169). 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 tyrosine amino acid residue is 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 and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 25, 2021

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