NM_000179.2(MSH6):c.3469G>T (p.Gly1157Cys) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Feb 26, 2020)

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.3469G>T (p.Gly1157Cys)]

NM_000179.2(MSH6):c.3469G>T (p.Gly1157Cys)

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000179.2(MSH6):c.3469G>T (p.Gly1157Cys)
  • NC_000002.12:g.47804940G>T
  • NG_007111.1:g.26794G>T
  • NG_008397.1:g.105736C>A
  • NM_000179.2:c.3469G>T
  • NM_001281492.1:c.3079G>T
  • NM_001281493.1:c.2563G>T
  • NM_001281494.1:c.2563G>T
  • NP_000170.1:p.Gly1157Cys
  • NP_001268421.1:p.Gly1027Cys
  • NP_001268422.1:p.Gly855Cys
  • NP_001268423.1:p.Gly855Cys
  • LRG_219t1:c.3469G>T
  • LRG_219:g.26794G>T
  • LRG_219p1:p.Gly1157Cys
  • NC_000002.11:g.48032079G>T
  • p.G1157C
Protein change:
dbSNP: rs587779264
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000179.2:c.3469G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.1:c.3079G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.1:c.2563G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.1:c.2563G>T - 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)
SCV000187253Ambry Geneticscriteria provided, single submitter
(Feb 26, 2020)
germlineclinical testing

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

Citation Link,

SCV000685408Color Health, Inccriteria provided, single submitter
Uncertain significance
(Apr 29, 2019)
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



Structure of the human MutSalpha DNA lesion recognition complex.

Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS.

Mol Cell. 2007 May 25;26(4):579-92.

PubMed [citation]

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

Details of each submission

From Ambry Genetics, SCV000187253.6

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


The p.G1157C pathogenic mutation (also known as c.3469G>T), located in coding exon 6 of the MSH6 gene, results from a G to T substitution at nucleotide position 3469. The glycine at codon 1157 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in several individuals whose Lynch-associated tumor demonstrated high microsatellite instability (MSI-H) and/or isolated loss of MSH6 protein expression on immunohistochemistry (IHC) (Ambry internal data). Based on an internal structural assessment, this alteration disrupts the local structure in the ATPase domain (Warren JJ et al. Mol. Cell. 2007 May;26:579-92). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

From Color Health, Inc, SCV000685408.3

#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: Feb 10, 2021

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