2-47806651-G-A

Variant names:

• chr2-47806651-G-A
• rs267608122
• NM_000179.3:c.4001G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000179.3(MSH6):​c.4001G>A​(p.Arg1334Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000275 in 1,455,180 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000711435: This variant was classified as Pathogenic on Sept 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108190.2). Consistent with this, tumors from patients harboring this variant showed absence of MSH6 protein (Hendriks 2004, Klarskov 2011)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1334W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:20
• Conservation: PhyloP100: 4.10
• Publications: 28 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000711435: This variant was classified as Pathogenic on Sept 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108190.2). Consistent with this, tumors from patients harboring this variant showed absence of MSH6 protein (Hendriks 2004, Klarskov 2011).; SCV004835194: A RT-PCR analysis of RNA derived from two carriers has reported out-of-frame skipping of exon 9 (UMD database, http://139.124.156.133/4D_molecules/UMD230309.html).; SCV004222027: Functional studies have demonstrated that this variant is damaging to protein function (PMIDs: 185669115 (2009), 28531214 (2017), and 30264118 (2018)).; SCV000580100: Functional studies have demonstrated the pathogenicity of this variant (Houlleberghs, 2017).; SCV000690430: A RT-PCR analysis of RNA derived from two carriers has reported out-of-frame skipping of exon 9 (UMD database, http://139.124.156.133/4D_molecules/UMD230309.html).; SCV000624960: Studies have shown that this missense change results in skipping of exon 9 and introduces a new termination codon (internal data).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47806651-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 233214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-47806651-G-A is Pathogenic according to our data. Variant chr2-47806651-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 89506.Status of the report is reviewed_by_expert_panel, 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.4001G>A	p.Arg1334Gln	missense splice_region	Exon 9 of 10	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.4097G>A	p.Arg1366Gln	missense splice_region	Exon 10 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.4007G>A	p.Arg1336Gln	missense splice_region	Exon 9 of 10	NP_001393742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.4001G>A	p.Arg1334Gln	missense splice_region	Exon 9 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*3348G>A		splice_region non_coding_transcript_exon	Exon 8 of 9	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000445503.5	TSL:1	n.*3348G>A		3_prime_UTR	Exon 8 of 9	ENSP00000405294.1	F8WAX8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455180 Hom.: 0 Cov.: 34 AF XY: 0.00000414 AC XY: 3 AN XY: 724216

African (AFR) AF: 0.00 AC: 0 AN: 33340

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109482

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000136 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
4	-	-	Lynch syndrome (4)
3	-	-	Lynch syndrome 5 (3)
2	-	-	Endometrial carcinoma (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Hereditary nonpolyposis colon cancer (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.7	L
PhyloP100		4.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.54
Sift	Benign	0.061	T
Sift4G	Benign	0.14	T
Polyphen		0.98	D
Vest4		0.56
MutPred		0.37		Loss of MoRF binding (P = 0.0301)
MVP		0.94
ClinPred		0.87	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.54
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.86		Position offset: 0

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

Other links and lift over

dbSNP: rs267608122; hg19: chr2-48033790; COSMIC: COSV52274318; COSMIC: COSV52274318;