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NM_000179.3(MSH6):c.668A>G (p.Asn223Ser) AND Carcinoma of colon

Germline classification:
Likely benign (1 submission)
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000500727.3

Allele description [Variation Report for NM_000179.3(MSH6):c.668A>G (p.Asn223Ser)]

NM_000179.3(MSH6):c.668A>G (p.Asn223Ser)

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.668A>G (p.Asn223Ser)
HGVS:
  • NC_000002.12:g.47798651A>G
  • NG_007111.1:g.20505A>G
  • NM_000179.3:c.668A>GMANE SELECT
  • NM_001281492.2:c.278A>G
  • NM_001281493.2:c.-239A>G
  • NM_001281494.2:c.-239A>G
  • NP_000170.1:p.Asn223Ser
  • NP_000170.1:p.Asn223Ser
  • NP_001268421.1:p.Asn93Ser
  • LRG_219t1:c.668A>G
  • LRG_219:g.20505A>G
  • LRG_219p1:p.Asn223Ser
  • NC_000002.11:g.48025790A>G
  • NM_000179.2:c.668A>G
Protein change:
N223S
Links:
dbSNP: rs587779316
NCBI 1000 Genomes Browser:
rs587779316
Molecular consequence:
  • NM_001281493.2:c.-239A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001281494.2:c.-239A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000179.3:c.668A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.278A>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Carcinoma of colon (CRC)
Synonyms:
Colonic carcinoma; Colon carcinoma
Identifiers:
MONDO: MONDO:0002032; MedGen: C0699790

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000592574Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Likely benignunknownclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes1not providednot providednot providednot providedclinical testing

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592574.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The p.Asn223Ser variant was identified in one database InSiGHT Colon Cancer Gene Variant Database 2X as an “uncertain” variant. It was not found in any of the following databases: dbSNP, 1000 Genomes Project, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight VariantWire database, and UMD. It was included in two bioinformatic studies that predicted the impact of missense variants in MSH6. Both studies concluded that the variant has no impact or is neutral (Terui 2013, Ali 2012). The p.Asn223 residue is not conserved in mammals or other vertebrates and the variant amino acid Serine (Ser) is present in zebrafish, increasing the likelihood that this variant does not have clinical significance. In addition, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. One of 5 in-silico splicing software predicts the creation of a 5' splice site, but this information is not very accurate. This variant was found in our laboratory to co-occur in with a known pathogenic variant c.3957dupA, increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.

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

Last Updated: Sep 29, 2024