2-47800544-A-T

Variant names:

• chr2-47800544-A-T
• rs34374438
• NM_000179.3:c.2561A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 3P and 7B. PM1 PP3 BP4_Moderate BP6 BS1

The NM_000179.3(MSH6):​c.2561A>T​(p.Lys854Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. K854N) has been classified as Likely benign. The gene MSH6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:11 O:1
• Conservation: PhyloP100: 7.39
• Publications: 30 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

Specifications for MSH6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 49 uncertain in NM_000179.3
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.13576648).
• BP6: Variant 2-47800544-A-T is Benign according to our data. Variant chr2-47800544-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 89289.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000355 (54/152276) while in subpopulation EAS AF = 0.00135 (7/5192). AF 95% confidence interval is 0.000632. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2561A>T	p.Lys854Met	missense	Exon 4 of 10	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.2657A>T	p.Lys886Met	missense	Exon 5 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.2567A>T	p.Lys856Met	missense	Exon 4 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.2561A>T	p.Lys854Met	missense	Exon 4 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*1908A>T		non_coding_transcript_exon	Exon 3 of 9	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000445503.5	TSL:1	n.*1908A>T		3_prime_UTR	Exon 3 of 9	ENSP00000405294.1	F8WAX8

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000393 AC: 98 AN: 249296 AF XY: 0.000340

Gnomad AFR exome AF: 0.000580

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00190

Gnomad EAS exome AF: 0.00169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.000196 AC: 286 AN: 1461412 Hom.: 0 Cov.: 34 AF XY: 0.000184 AC XY: 134 AN XY: 727026

African (AFR) AF: 0.000719 AC: 24 AN: 33396

American (AMR) AF: 0.000247 AC: 11 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26118

East Asian (EAS) AF: 0.000731 AC: 29 AN: 39694

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.000130 AC: 145 AN: 1111904

Other (OTH) AF: 0.000265 AC: 16 AN: 60366

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74470

African (AFR) AF: 0.000770 AC: 32 AN: 41568

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.000510

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000429 AC: 52

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Hereditary cancer-predisposing syndrome (5)
-	2	2	not provided (4)
-	1	1	not specified (3)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Carcinoma of colon (1)
-	1	-	Colorectal cancer (1)
-	1	-	Endometrial carcinoma;C1833477:Lynch syndrome 5;C5399763:Mismatch repair cancer syndrome 1 (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome 1 (1)
-	-	1	Lynch syndrome 5 (1)
-	1	-	MSH6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.14	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.55
MVP		0.95
ClinPred		0.11	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.79
Mutation Taster		=18/82	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: rs34374438; hg19: chr2-48027683; COSMIC: COSV105861230;