NM_000179.2(MSH6):c.2175C>G (p.Ile725Met) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Sep 24, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000556059.4

Allele description [Variation Report for NM_000179.2(MSH6):c.2175C>G (p.Ile725Met)]

NM_000179.2(MSH6):c.2175C>G (p.Ile725Met)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.2(MSH6):c.2175C>G (p.Ile725Met)
HGVS:
  • NC_000002.12:g.47800158C>G
  • NG_007111.1:g.22012C>G
  • NM_000179.2:c.2175C>G
  • NM_001281492.1:c.1785C>G
  • NM_001281493.1:c.1269C>G
  • NM_001281494.1:c.1269C>G
  • NP_000170.1:p.Ile725Met
  • NP_001268421.1:p.Ile595Met
  • NP_001268422.1:p.Ile423Met
  • NP_001268423.1:p.Ile423Met
  • LRG_219t1:c.2175C>G
  • LRG_219:g.22012C>G
  • LRG_219p1:p.Ile725Met
  • NC_000002.11:g.48027297C>G
  • P52701:p.Ile725Met
Protein change:
I423M
Links:
UniProtKB: P52701#VAR_043955; dbSNP: rs63750304
NCBI 1000 Genomes Browser:
rs63750304
Molecular consequence:
  • NM_000179.2:c.2175C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.1:c.1785C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.1:c.1269C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.1:c.1269C>G - 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
SCV000624731Invitaecriteria provided, single submitter
Uncertain significance
(Sep 24, 2020)
germlineclinical testing

PubMed (4)
[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

Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant.

Berends MJ, Wu Y, Sijmons RH, Mensink RG, van der Sluis T, Hordijk-Hos JM, de Vries EG, Hollema H, Karrenbeld A, Buys CH, van der Zee AG, Hofstra RM, Kleibeuker JH.

Am J Hum Genet. 2002 Jan;70(1):26-37.

PubMed [citation]
PMID:
11709755
PMCID:
PMC384896

Classification of mismatch repair gene missense variants with PON-MMR.

Ali H, Olatubosun A, Vihinen M.

Hum Mutat. 2012 Apr;33(4):642-50. doi: 10.1002/humu.22038.

PubMed [citation]
PMID:
22290698
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000624731.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces isoleucine with methionine at codon 725 of the MSH6 protein (p.Ile725Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs63750304, ExAC 0.005%). This variant has been reported in an individual affected with colorectal cancer (PMID: 11709755). ClinVar contains an entry for this variant (Variation ID: 89257). An algorithm developed specifically for the MSH6 gene (PMID: 22290698, 23621914), suggests that this missense change is likely to be tolerated. However, this prediction has not been confirmed by published functional studies and its 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: Mar 22, 2021

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