NM_000179.2(MSH6):c.2413A>G (p.Ile805Val) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Apr 13, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000564287.3

Allele description [Variation Report for NM_000179.2(MSH6):c.2413A>G (p.Ile805Val)]

NM_000179.2(MSH6):c.2413A>G (p.Ile805Val)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.2(MSH6):c.2413A>G (p.Ile805Val)
HGVS:
  • NC_000002.12:g.47800396A>G
  • NG_007111.1:g.22250A>G
  • NM_000179.2:c.2413A>G
  • NM_001281492.1:c.2023A>G
  • NM_001281493.1:c.1507A>G
  • NM_001281494.1:c.1507A>G
  • NP_000170.1:p.Ile805Val
  • NP_001268421.1:p.Ile675Val
  • NP_001268422.1:p.Ile503Val
  • NP_001268423.1:p.Ile503Val
  • LRG_219t1:c.2413A>G
  • LRG_219:g.22250A>G
  • LRG_219p1:p.Ile805Val
  • NC_000002.11:g.48027535A>G
Protein change:
I503V
Links:
dbSNP: rs928923556
NCBI 1000 Genomes Browser:
rs928923556
Molecular consequence:
  • NM_000179.2:c.2413A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.1:c.2023A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.1:c.1507A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.1:c.1507A>G - 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
SCV000662494Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Jul 21, 2016)
germlineclinical testing

Citation Link,

SCV000911133Color Health, Inccriteria provided, single submitter
Likely benign
(Apr 13, 2017)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

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, SCV000662494.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The p.I805V variant (also known as c.2413A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2413. The isoleucine at codon 805 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in several other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, the CoDP in silico tool predicts this alteration to have a minor impact on molecular function, with a score of 0.012 (Terui H et al. J. Biomed. Sci. 2013;20:25). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

From Color Health, Inc, SCV000911133.1

#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: Mar 22, 2021

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