NM_000179.3(MSH6):c.905G>A (p.Arg302Lys) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Sep 15, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000195580.7

Allele description [Variation Report for NM_000179.3(MSH6):c.905G>A (p.Arg302Lys)]

NM_000179.3(MSH6):c.905G>A (p.Arg302Lys)

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.905G>A (p.Arg302Lys)
HGVS:
  • NC_000002.12:g.47798888G>A
  • NG_007111.1:g.20742G>A
  • NM_000179.2:c.905G>A
  • NM_000179.3:c.905G>AMANE SELECT
  • NM_001281492.2:c.515G>A
  • NM_001281493.2:c.-2G>A
  • NM_001281494.2:c.-2G>A
  • NP_000170.1:p.Arg302Lys
  • NP_000170.1:p.Arg302Lys
  • NP_001268421.1:p.Arg172Lys
  • LRG_219t1:c.905G>A
  • LRG_219:g.20742G>A
  • LRG_219p1:p.Arg302Lys
  • NC_000002.11:g.48026027G>A
Protein change:
R172K
Links:
dbSNP: rs587781510
NCBI 1000 Genomes Browser:
rs587781510
Molecular consequence:
  • NM_001281493.2:c.-2G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001281494.2:c.-2G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000179.2:c.905G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000179.3:c.905G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.515G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000254337Invitaecriteria provided, single submitter
Uncertain significance
(Sep 15, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families.

Grandval P, Fabre AJ, Gaildrat P, Baert-Desurmont S, Buisine MP, Ferrari A, Wang Q, BĂ©roud C, Olschwang S.

Database (Oxford). 2013 May 31;2013:bat036. doi: 10.1093/database/bat036. Print 2013.

PubMed [citation]
PMID:
23729658
PMCID:
PMC3668602

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000254337.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces arginine with lysine at codon 302 of the MSH6 protein (p.Arg302Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs587781510, ExAC 0.002%). This variant has been reported in an individual in the Universal Mutation Database (PMID: 23729658). However, in that individual a pathogenic variant was also identified in MSH6, which suggests that this c.905G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 216324). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 30, 2021

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