NM_000179.2(MSH6):c.2175C>G (p.Ile725Met) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Mar 22, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

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

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

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000179.2(MSH6):c.2175C>G (p.Ile725Met)
  • 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:
UniProtKB: P52701#VAR_043955; dbSNP: rs63750304
NCBI 1000 Genomes Browser:
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]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000662560Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Mar 22, 2017)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000908260Color Health, Inccriteria provided, single submitter
Likely benign
(Feb 22, 2016)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



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]

BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes.

Domingo E, Niessen RC, Oliveira C, Alhopuro P, Moutinho C, EspĂ­n E, Armengol M, Sijmons RH, Kleibeuker JH, Seruca R, Aaltonen LA, Imai K, Yamamoto H, Schwartz S Jr, Hofstra RM.

Oncogene. 2005 Jun 2;24(24):3995-8.

PubMed [citation]
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000662560.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)


The p.I725M variant (also known as c.2175C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2175. The isoleucine at codon 725 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in an individual diagnosed with colon cancer at 36, whose tumor showed presence of the MLH1, MSH2, and MSH6 proteins on immunohistochemistry, low microsatellite instability, and absence of the BRAF V600E mutation (Berends MJ et al. Am. J. Hum. Genet., 2002 Jan;70:26-37; Domingo E et al. Oncogene, 2005 Jun;24:3995-8). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, the CoDP in silico tool predicts this alteration to have a minor impact on molecular function, with a score of 0.000 (Terui H et al. J. Biomed. Sci. 2013 Apr;20:25). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000908260.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 22, 2021

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