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

Clinical significance:Likely benign (Last evaluated: Apr 30, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000757926.2

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:
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
SCV000886444University of Washington Department of Laboratory Medicine, University of Washingtoncriteria provided, single submitter
Likely benign
(Apr 30, 2018)
germlineresearch

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

SCV001550941Department 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 providedgermlinenonot provided1not providednot providednoresearch
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

Tsai GJ, Rañola 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

Details of each submission

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000886444.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednoresearch PubMed (1)

Description

The MSH6 variant designated as NM_000179.2:c.1822A>G (p.Ile608Val) is classified as likely benign. Based on in-silico scores the variant has a prior probability of pathogenicity of 10% (Thompson et al., 2013, PMID:22949379). Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303). Analysis of one family gave a likelihood ratio of 0.34 to 1 that this allele explains cancer in the family (Thompson, et al., 2003, PMID:2900794). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH6 function or modify cancer risk for Lynch syndrome. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001550941.1

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

Description

The MSH6 p.Ile608Val variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome-related cancer and/or colorectal polyps (Yurgelun 2015). In this study, the variant co-occurred with a pathogenic MUTYH variant (c.734G>A, p.Arg245His) in the affected individual. The variant was also identified in dbSNP (ID: rs201613780) as “With Uncertain significance allele”, ClinVar (classified as likely benign by University of Washington Dept. of Laboratory Medicine and as uncertain significance by GeneDx, Invitae, Ambry Genetics, Color and Integrated Genetics/Laboratory Corp. of America). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 8 of 276892 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017); observed in the following populations: European Non-Finnish in 7 of 126468 chromosomes (freq: 0.00006) and European Finnish in 1 of 25790 chromosomes (freq: 0.00004), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian or South Asian populations. The p.Ile608 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Val variant impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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