NM_000179.3(MSH6):c.1081C>T (p.Arg361Cys) AND Lynch syndrome

Clinical significance:Likely benign (Last evaluated: May 1, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000758606.2

Allele description [Variation Report for NM_000179.3(MSH6):c.1081C>T (p.Arg361Cys)]

NM_000179.3(MSH6):c.1081C>T (p.Arg361Cys)

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.1081C>T (p.Arg361Cys)
HGVS:
  • NC_000002.12:g.47799064C>T
  • NG_007111.1:g.20918C>T
  • NM_000179.2:c.1081C>T
  • NM_000179.3:c.1081C>TMANE SELECT
  • NM_001281492.2:c.691C>T
  • NM_001281493.2:c.175C>T
  • NM_001281494.2:c.175C>T
  • NP_000170.1:p.Arg361Cys
  • NP_000170.1:p.Arg361Cys
  • NP_001268421.1:p.Arg231Cys
  • NP_001268422.1:p.Arg59Cys
  • NP_001268423.1:p.Arg59Cys
  • LRG_219t1:c.1081C>T
  • LRG_219:g.20918C>T
  • LRG_219p1:p.Arg361Cys
  • NC_000002.11:g.48026203C>T
  • p.R361C
Protein change:
R231C
Links:
dbSNP: rs587782651
NCBI 1000 Genomes Browser:
rs587782651
Molecular consequence:
  • NM_000179.2:c.1081C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000179.3:c.1081C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.691C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.2:c.175C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.2:c.175C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Lynch syndrome
Synonyms:
Familial nonpolyposis colon cancer
Identifiers:
MONDO: MONDO:0005835; MedGen: C4552100; OMIM: PS120435

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000887360University of Washington Department of Laboratory Medicine, University of Washingtoncriteria provided, single submitter
Likely benign
(May 1, 2018)
somaticclinical testing

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

SCV001551706Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedUncertain significanceunknownclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedsomaticyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes.

Shirts BH, Konnick EQ, Upham S, Walsh T, Ranola JMO, Jacobson AL, King MC, Pearlman R, Hampel H, Pritchard CC.

Am J Hum Genet. 2018 Jul 5;103(1):19-29. doi: 10.1016/j.ajhg.2018.05.001. Epub 2018 Jun 7.

PubMed [citation]
PMID:
29887214
PMCID:
PMC6035155

Details of each submission

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000887360.1

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

Description

MSH6 NM_000179.2:c.1081C>T has a 1.8% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.

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

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001551706.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The MSH6 p.Arg361Cys variant was not identified in the literature nor was it identified in the COGR, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs587782651) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Color Genomics, Integrated Genetics/Laboratory Corporation of America), and in Cosmic (1x found in prostate tissue). The variant was identified in control databases in 13 of 245822 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 5478 chromosomes (freq: 0.0002), Latino in 11 of 33560 chromosomes (freq: 0.0003), and South Asian in 1 of 30780 chromosomes (freq: 0.00003); it was not observed in the African, European, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Arg361 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Oct 30, 2021

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