chr2-47799221-G-C

Variant names:

• chr2-47799221-G-C
• rs786201049
• NM_000179.3:c.1238G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000179.3(MSH6):​c.1238G>C​(p.Trp413Ser) 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. 13/22 in silico tools predict a damaging 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. W413C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.74
• Publications: 4 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 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 48 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 chr2-47799222-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 818679.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 2-47799221-G-C is Pathogenic according to our data. Variant chr2-47799221-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 237131.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.1238G>C	p.Trp413Ser	missense	Exon 4 of 10	NP_000170.1
	MSH6	NM_001406795.1		c.1334G>C	p.Trp445Ser	missense	Exon 5 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.1244G>C	p.Trp415Ser	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.1238G>C	p.Trp413Ser	missense	Exon 4 of 10	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.*585G>C		non_coding_transcript_exon	Exon 3 of 9	ENSP00000405294.1
	MSH6	ENST00000445503.5	TSL:1	n.*585G>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: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 413 of the MSH6 protein (p.Trp413Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 237131). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MSH6 protein function with a positive predictive value of 95%. This variant disrupts the p.Trp413 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been observed in individuals with MSH6-related conditions (external communication, internal data), which suggests that this may be a clinically significant amino acid residue. 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.

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 05, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W413S variant (also known as c.1238G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 1238. The tryptophan at codon 413 is replaced by serine, an amino acid with highly dissimilar properties. This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability (MSI-H) and loss of MSH6 expression by immunohistochemistry (IHC; Li S et al. J. Med. Genet. 2020 Jan;57:62-69; Hájková N et al. Transl Res, 2023 Oct;260:61-68; Ambry internal data). In addition, this variant has been identified in probands whose Lynch syndrome-associated tumor was microsatellite stable (MSS) or MSI-L but demonstrated partial loss of MSH2/MSH6 or MSH6 expression by IHC, respectively (Kiyozumi Y et al. Cancer Epidemiol Biomarkers Prev, 2021 Jan;30:166-174). Another variant at the same codon, p.W413C (c.1239G>C), has been identified in individuals with features consistent with MSH6-related Lynch syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-14	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.79		Gain of disorder (P = 0.0024)
MVP		0.99
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.87
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs786201049; hg19: chr2-48026360;