NM_000179.3(MSH6):c.1474A>G (p.Met492Val) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Oct 18, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000587662.2

Allele description [Variation Report for NM_000179.3(MSH6):c.1474A>G (p.Met492Val)]

NM_000179.3(MSH6):c.1474A>G (p.Met492Val)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.1474A>G (p.Met492Val)
Other names:
p.M492V:ATG>GTG
HGVS:
  • NC_000002.12:g.47799457A>G
  • NG_007111.1:g.21311A>G
  • NM_000179.2:c.1474A>G
  • NM_000179.3:c.1474A>GMANE SELECT
  • NM_001281492.1:c.1084A>G
  • NM_001281493.1:c.568A>G
  • NM_001281494.1:c.568A>G
  • NP_000170.1:p.Met492Val
  • NP_000170.1:p.Met492Val
  • NP_001268421.1:p.Met362Val
  • NP_001268422.1:p.Met190Val
  • NP_001268423.1:p.Met190Val
  • LRG_219t1:c.1474A>G
  • LRG_219:g.21311A>G
  • LRG_219p1:p.Met492Val
  • NC_000002.11:g.48026596A>G
  • P52701:p.Met492Val
  • p.M492V
Protein change:
M190V
Links:
UniProtKB: P52701#VAR_042275; dbSNP: rs61754783
NCBI 1000 Genomes Browser:
rs61754783
Molecular consequence:
  • NM_000179.2:c.1474A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000179.3:c.1474A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.1:c.1084A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.1:c.568A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.1:c.568A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000149283GeneDxcriteria provided, single submitter
Uncertain significance
(Oct 18, 2018)
germlineclinical testing

Citation Link,

SCV000695784Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Aug 24, 2016)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000805844PreventionGenetics,PreventionGeneticscriteria provided, single submitter
Uncertain significance
(May 15, 2017)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants.

Drost M, Zonneveld JB, van Hees S, Rasmussen LJ, Hofstra RM, de Wind N.

Hum Mutat. 2012 Mar;33(3):488-94. doi: 10.1002/humu.22000. Epub 2011 Dec 29.

PubMed [citation]
PMID:
22102614

Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene.

Wagner A, Barrows A, Wijnen JT, van der Klift H, Franken PF, Verkuijlen P, Nakagawa H, Geugien M, Jaghmohan-Changur S, Breukel C, Meijers-Heijboer H, Morreau H, van Puijenbroek M, Burn J, Coronel S, Kinarski Y, Okimoto R, Watson P, Lynch JF, de la Chapelle A, Lynch HT, Fodde R.

Am J Hum Genet. 2003 May;72(5):1088-100. Epub 2003 Mar 25.

PubMed [citation]
PMID:
12658575
PMCID:
PMC1180263
See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000149283.14

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant is denoted MSH6 c.1474A>G at the cDNA level, p.Met492Val (M492V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). Although this variant was observed in three individuals with colorectal cancer from families suspicious for Lynch syndrome, as well as at least one individual with ovarian cancer (Wagner 2003, Nilbert 2009, Okkels 2012, Pal 2012), in vitro analysis demonstrated mismatch repair activity comparable to wild-type (Drost 2012). This variant has also been reported in individuals with pancreatic neuroendocrine tumor, breast cancer, or thyroid cancer (Shindo 2017, Lovejoy 2018, Yehia 2018). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies MSH6 Met492Val as a variant of uncertain significance due to insufficient evidence for classification (Thompson 2014). MSH6 Met492Val was observed at an allele frequency of 0.04% (11/25,786) in individuals of Finnish ancestry in large population cohorts (Lek 2016). This variant is located within the mismatch binding domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Met492Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695784.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: The MSH6 c.1474A>G (p.Met492Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 7/121326 control chromosomes at a frequency of 0.0000577, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant has been reported in the literature in patients/families with suspected Lynch Syndrome (Nilbert_2009, Okkels_2012, Wagner_2003) and ovarian cancer (Pal_2012), without strong evidence for causality (lacking co-segregation data). Despite its presence in affected individuals, an in vitro assay showed the variant to have similar MMR activity compared to WT (Drost_2011). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence becomes available.

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

From PreventionGenetics,PreventionGenetics, SCV000805844.1

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

Last Updated: Jul 7, 2021

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