NM_000179.3:c.2905T>C

Variant names:

• chr2-47800888-T-C
• rs1348956744
• NM_000179.3:c.2905T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_000179.3(MSH6):​c.2905T>C​(p.Tyr969His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y969F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.99
• Publications: 0 publications found

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]

FBXO11 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 40 uncertain in NM_000179.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47800889-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 89321.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801
• PP5: Variant 2-47800888-T-C is Pathogenic according to our data. Variant chr2-47800888-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433916.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.2905T>C	p.Tyr969His	missense	Exon 4 of 10	NP_000170.1
	MSH6	NM_001406795.1		c.3001T>C	p.Tyr1001His	missense	Exon 5 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.2911T>C	p.Tyr971His	missense	Exon 4 of 10	NP_001393742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.2905T>C	p.Tyr969His	missense	Exon 4 of 10	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.*2252T>C		non_coding_transcript_exon	Exon 3 of 9	ENSP00000405294.1
	MSH6	ENST00000445503.5	TSL:1	n.*2252T>C		3_prime_UTR	Exon 3 of 9	ENSP00000405294.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452766 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 721814

African (AFR) AF: 0.00 AC: 0 AN: 32966

American (AMR) AF: 0.00 AC: 0 AN: 42942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25706

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108066

Other (OTH) AF: 0.00 AC: 0 AN: 59948

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Oct 21, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr969 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20587412, 16813607, 19723918, 23621914). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 433916). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 969 of the MSH6 protein (p.Tyr969His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine.

Carcinoma of colon Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Tyr969His variant was not identified in the literature nor was it identified in the dbSNP, MutDB, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, “MMR Gene Unclassified Variants Database”, COSMIC, ClinVar and UMD databases. The p.Tyr969 residue is conserved across mammals, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Tyr969His variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.64		Loss of sheet (P = 0.0817)
MVP		0.96
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.81
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs1348956744; hg19: chr2-48028027;