NM_000179.3(MSH6):c.3G>T (p.Met1Ile) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Likely pathogenic (Last evaluated: Aug 25, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000793054.2

Allele description [Variation Report for NM_000179.3(MSH6):c.3G>T (p.Met1Ile)]

NM_000179.3(MSH6):c.3G>T (p.Met1Ile)

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.3G>T (p.Met1Ile)
HGVS:
  • NC_000002.12:g.47783236G>T
  • NG_007111.1:g.5090G>T
  • NM_000179.2:c.3G>T
  • NM_000179.3:c.3G>TMANE SELECT
  • NM_001281492.2:c.3G>T
  • NM_001281493.2:c.-734G>T
  • NP_000170.1:p.Met1Ile
  • NP_000170.1:p.Met1Ile
  • NP_001268421.1:p.Met1Ile
  • LRG_219t1:c.3G>T
  • LRG_219:g.5090G>T
  • LRG_219p1:p.Met1Ile
  • NC_000002.11:g.48010375G>T
Protein change:
M1I
Links:
dbSNP: rs876660095
NCBI 1000 Genomes Browser:
rs876660095
Molecular consequence:
  • NM_001281493.2:c.-734G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000179.3:c.3G>T - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001281492.2:c.3G>T - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_000179.2:c.3G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000179.3:c.3G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.3G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MedGen: C0009405; Orphanet: 443090

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000932389Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 25, 2019)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

LOVD v.2.0: the next generation in gene variant databases.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT.

Hum Mutat. 2011 May;32(5):557-63. doi: 10.1002/humu.21438. Epub 2011 Feb 22.

PubMed [citation]
PMID:
21520333

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000932389.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change affects the initiator methionine of the MSH6 mRNA. While this variant may disrupt protein translation of the MSH6 mRNA, an alternate in-frame methionine downstream of the original initiator codon located at codon 100 could potentially rescue translation initiation. However, experimental studies have not been performed to determine if an alternative initiator codon is utilized. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Lynch syndrome in the Leiden Open-source Variation Database (PMID: 21520333). Also, this variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual with features consistent with constitutional mismatch repair deficiency syndrome (PMID: 21520333). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 232954). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Oct 30, 2021

Support Center