NM_000179.3(MSH6):c.2827G>T (p.Asp943Tyr) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Sep 24, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000131640.10

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_000179.2:c.2827G>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
  • p.D943Y
Protein change:
D641Y
Links:
dbSNP: rs143520357
NCBI 1000 Genomes Browser:
rs143520357
Molecular consequence:
  • NM_000179.2:c.2827G>T - missense variant - [Sequence Ontology: SO:0001583]
  • 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]
Observations:
1

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000186664Ambry Geneticscriteria provided, single submitter
Likely benign
(Aug 15, 2019)
germlineclinical testing

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

Citation Link,

SCV000537570Color Health, Inccriteria provided, single submitter
Uncertain significance
(Sep 24, 2019)
germlineclinical testing

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

Description

This missense variant replaces aspartic acid with tyrosine at codon 943 of the MSH6 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25186627) and pancreatic cancer (PMID: 25479140). This variant has been identified in 13/281888 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

SCV000537570

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein.

Terui H, Akagi K, Kawame H, Yura K.

J Biomed Sci. 2013 Apr 28;20:25. doi: 10.1186/1423-0127-20-25.

PubMed [citation]
PMID:
23621914
PMCID:
PMC3651391

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Ambry Genetics, SCV000186664.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting benign classification;Other strong data supporting benign classification;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000537570.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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