NM_000179.3:c.3416G>T

Variant names:

• chr2-47803663-G-T
• rs1316409501
• NM_000179.3:c.3416G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000179.3(MSH6):​c.3416G>T​(p.Gly1139Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.97

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47803663-G-T is Pathogenic according to our data. Variant chr2-47803663-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 433923.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3416G>T	p.Gly1139Val	missense_variant	Exon 5 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3416G>T	p.Gly1139Val	missense_variant	Exon 5 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 26, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G1139V variant (also known as c.3416G>T), located in coding exon 5 of the MSH6 gene, results from a G to T substitution at nucleotide position 3416. The glycine at codon 1139 is replaced by valine, an amino acid with dissimilar properties. This alteration was identified along with a somatic likely pathogenic MSH6 variant in an individual whose colorectal tumor displayed isolated loss of MSH6 expression by immunohistochemistry (IHC) and in an individual with endometrial cancer that also showed isolated loss of MSH6 expression by IHC (Ambry internal data). Another alteration at the same codon, p.G1139S, has been reported in two unrelated individuals with early-onset MSI-H colorectal cancer that displayed loss of MSH2 and/or MSH6 on IHC and demonstrated deficient mismatch repair activity in several functional studies (Woods MO et al. Clin. Cancer Res., 2005 Oct;11:6853-61; Steinke V et al. Eur. J. Hum. Genet., 2008 May;16:587-92; Drost M et al. Hum. Mutat., 2012 Mar;33:488-94; Wielders EA et al. PLoS ONE, 2013 Sep;8:e74766; Houlleberghs H et al. PLoS Genet., 2017 May;13:e1006765). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Endometrial carcinoma Pathogenic:1

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Gly1139Val variant was identified in UMD 1X as an unclassified variant; however, it was not identified in the literature, nor was it identified in the dbSNP, HGMD, COSMIC, MutDB, MMR DB, MMRUV DB or InSiGHT Colon Cancer databases. The p.Gly1139 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) suggest that the variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Another variant has been reported at this position c.3415G>A (p.Gly1139Ser) in an individual with MSI-high and MSH2/MSH6 deficient tumours (Woods 2005). Furthermore, the p.Gly1139Ser variant is found in the P-loop of the ATP binding domain required for hydrolysis of ATP and functional studies supported a pathogenic role for this variant and increasing the likelihood that another variant at the same residue may have an impact on protein function (Woods 2005, Studamire 1998, Drost 2011). The individual reported here had a tumour that was MSI-unstable and deficient in MSH6 further suggesting a pathogenic role for this variant. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Feb 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MSH6-related conditions (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 433923). 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. 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. This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1139 of the MSH6 protein (p.Gly1139Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.27	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Pathogenic	0.95	D
Sift4G	Uncertain	0.020	D
Vest4		0.52
MVP		0.93
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1316409501; hg19: chr2-48030802;