2-47800542-G-C

Variant names:

• chr2-47800542-G-C
• rs765873566
• NM_000179.3:c.2559G>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1 PM2 PP5_Very_Strong

The NM_000179.3(MSH6):​c.2559G>C​(p.Lys853Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K853R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.165
• Publications: 1 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: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_000179.3 (MSH6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47800542-G-C is Pathogenic according to our data. Variant chr2-47800542-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 486911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.2559G>C	p.Lys853Asn	missense	Exon 4 of 10	NP_000170.1
	MSH6	NM_001406795.1		c.2655G>C	p.Lys885Asn	missense	Exon 5 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.2565G>C	p.Lys855Asn	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.2559G>C	p.Lys853Asn	missense	Exon 4 of 10	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.*1906G>C		non_coding_transcript_exon	Exon 3 of 9	ENSP00000405294.1
	MSH6	ENST00000445503.5	TSL:1	n.*1906G>C		3_prime_UTR	Exon 3 of 9	ENSP00000405294.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Nov 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 853 of the MSH6 protein (p.Lys853Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lynch syndrome-associated cancer (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 486911). 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 not expected to disrupt MSH6 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 11, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K853N variant (also known as c.2559G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 2559. The lysine at codon 853 is replaced by asparagine, an amino acid with similar properties. This variant has been detected in multiple families meeting Amsterdam criteria and co-segregated with disease in at least one family and tumor results for several affected family members showed isolated loss of MSH6 expression on immunohistochemistry (IHC) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.076
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.17
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.56
MutPred		0.48		Loss of ubiquitination at K853 (P = 0.0362)
MVP		0.92
ClinPred		0.99	D
GERP RS		-0.88
Varity_R		0.84
gMVP		0.50
Mutation Taster		=35/65	disease causing (ClinVar)

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: rs765873566; hg19: chr2-48027681;