NM_000179.2(MSH6):c.257C>T (p.Thr86Ile) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Apr 17, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000572033.4

Allele description [Variation Report for NM_000179.2(MSH6):c.257C>T (p.Thr86Ile)]

NM_000179.2(MSH6):c.257C>T (p.Thr86Ile)

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.257C>T (p.Thr86Ile)
HGVS:
  • NC_000002.12:g.47783490C>T
  • NG_007111.1:g.5344C>T
  • NM_000179.2:c.257C>T
  • NM_001281492.1:c.237+20C>T
  • NM_001281493.1:c.-480C>T
  • NP_000170.1:p.Thr86Ile
  • LRG_219t1:c.257C>T
  • LRG_219:g.5344C>T
  • LRG_219p1:p.Thr86Ile
  • NC_000002.11:g.48010629C>T
Protein change:
T86I
Links:
dbSNP: rs768444916
NCBI 1000 Genomes Browser:
rs768444916
Molecular consequence:
  • NM_001281493.1:c.-480C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001281492.1:c.237+20C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000179.2:c.257C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000664870Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Apr 17, 2020)
germlineclinical testing

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

Citation Link,

SCV000903779Color Health, Inccriteria provided, single submitter
Likely benign
(Jan 12, 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

Citations

PubMed

Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.

Pearlman R, Frankel WL, Swanson B, Zhao W, Yilmaz A, Miller K, Bacher J, Bigley C, Nelsen L, Goodfellow PJ, Goldberg RM, Paskett E, Shields PG, Freudenheim JL, Stanich PP, Lattimer I, Arnold M, Liyanarachchi S, Kalady M, Heald B, Greenwood C, Paquette I, et al.

JAMA Oncol. 2017 Apr 1;3(4):464-471. doi: 10.1001/jamaoncol.2016.5194.

PubMed [citation]
PMID:
27978560
PMCID:
PMC5564179

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]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Ambry Genetics, SCV000664870.3

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

Description

The p.T86I variant (also known as c.257C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 257. The threonine at codon 86 is replaced by isoleucine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with mismatch repair proficient colon cancer and multiple colon polyps at age 44 (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

From Color Health, Inc, SCV000903779.1

#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: Aug 19, 2021

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