NM_000179.3(MSH6):c.1822A>G (p.Ile608Val) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Oct 21, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000196510.9

Allele description [Variation Report for NM_000179.3(MSH6):c.1822A>G (p.Ile608Val)]

NM_000179.3(MSH6):c.1822A>G (p.Ile608Val)

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.1822A>G (p.Ile608Val)
Other names:
p.I608V:ATT>GTT
HGVS:
  • NC_000002.12:g.47799805A>G
  • NG_007111.1:g.21659A>G
  • NM_000179.2:c.1822A>G
  • NM_000179.3:c.1822A>GMANE SELECT
  • NM_001281492.2:c.1432A>G
  • NM_001281493.2:c.916A>G
  • NM_001281494.2:c.916A>G
  • NP_000170.1:p.Ile608Val
  • NP_000170.1:p.Ile608Val
  • NP_001268421.1:p.Ile478Val
  • NP_001268422.1:p.Ile306Val
  • NP_001268423.1:p.Ile306Val
  • LRG_219t1:c.1822A>G
  • LRG_219:g.21659A>G
  • LRG_219p1:p.Ile608Val
  • NC_000002.11:g.48026944A>G
Protein change:
I306V
Links:
dbSNP: rs201613780
NCBI 1000 Genomes Browser:
rs201613780
Molecular consequence:
  • NM_000179.2:c.1822A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000179.3:c.1822A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.1432A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.2:c.916A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.2:c.916A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000254283Invitaecriteria provided, single submitter
Uncertain significance
(Oct 21, 2020)
germlineclinical testing

PubMed (3)
[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

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S.

Gastroenterology. 2015 Sep;149(3):604-13.e20. doi: 10.1053/j.gastro.2015.05.006. Epub 2015 May 14.

PubMed [citation]
PMID:
25980754
PMCID:
PMC4550537

Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.

Tsai GJ, RaƱola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, Bowen DJ, Shirts BH.

Genet Med. 2019 Jun;21(6):1435-1442. doi: 10.1038/s41436-018-0335-7. Epub 2018 Oct 30.

PubMed [citation]
PMID:
30374176
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000254283.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces isoleucine with valine at codon 608 of the MSH6 protein (p.Ile608Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs201613780, ExAC <0.01%). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 25980754) and in an individual with breast cancer (PMID: 30374176). ClinVar contains an entry for this variant (Variation ID: 182626). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0). The valine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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