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NM_000179.3(MSH6):c.3416G>A (p.Gly1139Asp) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 28, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000704717.8

Allele description [Variation Report for NM_000179.3(MSH6):c.3416G>A (p.Gly1139Asp)]

NM_000179.3(MSH6):c.3416G>A (p.Gly1139Asp)

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.3416G>A (p.Gly1139Asp)
HGVS:
  • NC_000002.12:g.47803663G>A
  • NG_007111.1:g.25517G>A
  • NM_000179.3:c.3416G>AMANE SELECT
  • NM_001281492.2:c.3026G>A
  • NM_001281493.2:c.2510G>A
  • NM_001281494.2:c.2510G>A
  • NP_000170.1:p.Gly1139Asp
  • NP_000170.1:p.Gly1139Asp
  • NP_001268421.1:p.Gly1009Asp
  • NP_001268422.1:p.Gly837Asp
  • NP_001268423.1:p.Gly837Asp
  • LRG_219t1:c.3416G>A
  • LRG_219:g.25517G>A
  • LRG_219p1:p.Gly1139Asp
  • NC_000002.11:g.48030802G>A
  • NM_000179.2:c.3416G>A
Protein change:
G1009D
Links:
dbSNP: rs1316409501
NCBI 1000 Genomes Browser:
rs1316409501
Molecular consequence:
  • NM_000179.3:c.3416G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.3026G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.2:c.2510G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.2:c.2510G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MeSH: D003123; MedGen: C0009405

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000833676Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Aug 28, 2023) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance.

Wai HA, Lord J, Lyon M, Gunning A, Kelly H, Cibin P, Seaby EG, Spiers-Fitzgerald K, Lye J, Ellard S, Thomas NS, Bunyan DJ, Douglas AGL, Baralle D; Splicing and disease working group..

Genet Med. 2020 Jun;22(6):1005-1014. doi: 10.1038/s41436-020-0766-9. Epub 2020 Mar 3. Erratum in: Genet Med. 2020 Jun;22(6):1129. doi: 10.1038/s41436-020-0789-2.

PubMed [citation]
PMID:
32123317
PMCID:
PMC7272326

Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome.

Drost M, Tiersma Y, Glubb D, Kathe S, van Hees S, Calléja F, Zonneveld JBM, Boucher KM, Ramlal RPE, Thompson BA, Rasmussen LJ, Greenblatt MS, Lee A, Spurdle AB, Tavtigian SV, de Wind N.

Genet Med. 2020 May;22(5):847-856. doi: 10.1038/s41436-019-0736-2. Epub 2020 Jan 22.

PubMed [citation]
PMID:
31965077
PMCID:
PMC7200593
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000833676.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 32123317). Experimental studies have shown that this missense change affects MSH6 function (PMID: 31965077). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 581014). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1139 of the MSH6 protein (p.Gly1139Asp).

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

Last Updated: Oct 8, 2024