NM_000179.3(MSH6):c.2827G>T (p.Asp943Tyr) AND Lynch syndrome

Clinical significance:Uncertain significance

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001356309.1

Allele description [Variation Report for NM_000179.3(MSH6):c.2827G>T (p.Asp943Tyr)]

NM_000179.3(MSH6):c.2827G>T (p.Asp943Tyr)

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.2827G>T (p.Asp943Tyr)
Other names:
p.D943Y:GAC>TAC
HGVS:
  • NC_000002.12:g.47800810G>T
  • NG_007111.1:g.22664G>T
  • NM_000179.3:c.2827G>TMANE SELECT
  • NM_001281492.2:c.2437G>T
  • NM_001281493.2:c.1921G>T
  • NM_001281494.2:c.1921G>T
  • NP_000170.1:p.Asp943Tyr
  • NP_000170.1:p.Asp943Tyr
  • NP_001268421.1:p.Asp813Tyr
  • NP_001268422.1:p.Asp641Tyr
  • NP_001268423.1:p.Asp641Tyr
  • LRG_219t1:c.2827G>T
  • LRG_219:g.22664G>T
  • LRG_219p1:p.Asp943Tyr
  • NC_000002.11:g.48027949G>T
  • NM_000179.2:c.2827G>T
  • p.D943Y
Protein change:
D641Y
Links:
dbSNP: rs143520357
NCBI 1000 Genomes Browser:
rs143520357
Molecular consequence:
  • NM_000179.3:c.2827G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.2437G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.2:c.1921G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.2:c.1921G>T - 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
SCV001551439Department 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 providedunknownyesnot providednot 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), SCV001551439.1

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

Description

The MSH6 p.Asp943Tyr variant was identified in 1 of 580 proband chromosomes (frequency: 0.002) from individuals or families with pancreatic cancer (Grant_2015_25479140). A bioinformatics tool, CoDP (Combination of the Different Properties) integrating the prediction results of three methods (MAPP, PolyPhen-2 and SIFT) and two structural properties, found the variant impacted the MSH6 protein (Terui_2013_23621914). The variant was also identified in dbSNP (ID: rs143520357) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color Genomics), Clinvitae (4x), and in control databases in 13 of 276196 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). It was identified in the European Non-Finnish population in 13 of 125940 chromosomes (freq: 0.0001); and was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish and South Asian populations. The variant was not identified in the COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database or the Insight Hereditary Tumors Database. The p.Asp943 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Tyr variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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: Dec 4, 2021

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