rs876661174

Positions:

• chr2-47806597-G-A
• chr2-47806597-G-C
• chr2-47806597-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The ENST00000234420.11(MSH6):​c.3947G>A​(p.Gly1316Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1316R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 ENST00000234420.11 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 8.11

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47806596-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234901.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 2-47806597-G-A is Pathogenic according to our data. Variant chr2-47806597-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 490016.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3947G>A	p.Gly1316Glu	missense_variant	9/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3947G>A	p.Gly1316Glu	missense_variant	9/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 03, 2022	This missense variant replaces glycine with glutamic acid at codon 1316 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer with tumors showing microsatellite instability and loss of MSH6 expression (PMID: 24100870). This variant has not been identified 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 07, 2018	The p.G1316E variant (also known as c.3947G>A), located in coding exon 9 of the MSH6 gene, results from a G to A substitution at nucleotide position 3947. The glycine at codon 1316 is replaced by glutamic acid, an amino acid with similar properties. This alteration was identified once in a study of MSH6 germline variants from a cohort of 1720 colon cancer patients. The patient had colon cancer at age 49 and her tumor was MSI-H. Also, immunohistochemistry (IHC) revealed absent MSH6 staining in her tumor and MLH1 promoter hypermethylation as well as BRAF analyses were negative (Terui H et al. Oncol. Rep., 2013 Dec;30:2909-16). This alteration was also identified as somatic in a MSI-H colon tumor that displayed loss of MSH6 staining on IHC (Ambry internal data). Based on an internal structural assessment, this alteration results in disruption of the C-terminal MSH2-MSH6 interface (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, the CoDP in silico tool predicts this alteration to likely impair molecular function, with a score of 0.999 (Terui H et al. J. Biomed. Sci. 2013 Apr;20:25). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 07, 2018

This variant has been observed in an individual affected with colorectal cancer (PMID: 24100870). ClinVar contains an entry for this variant (Variation ID: 490016). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 1316 of the MSH6 protein (p.Gly1316Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. 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 variant disrupts the p.Gly1316 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 24440087), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;.;T;D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.5	.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.0	.;D;.;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	.;D;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.94
MutPred		0.74		.;.;.;Loss of MoRF binding (P = 0.0235);.;
MVP		0.96
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.98
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876661174; hg19: chr2-48033736;