2-47798756-T-C

Variant names:

• chr2-47798756-T-C
• rs1553412195
• NM_000179.3:c.773T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000179.3(MSH6):​c.773T>C​(p.Ile258Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I258V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 0.216
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045629233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.773T>C	p.Ile258Thr	missense_variant	Exon 4 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.773T>C	p.Ile258Thr	missense_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Mar 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I258T variant (also known as c.773T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 773. The isoleucine at codon 258 is replaced by threonine, an amino acid with similar properties. This variant has been identified in conjunction with MLH1 c.1989G>A in a cohort of Swedish families with features consistent with Lynch syndrome (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Feb 23, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_supporting, BP4 c.773T>C, located in exon 4 of the MSH6 gene, is predicted to result in the substitution of Isoleucine by Threonine at codon 258, p.(Ile258Thr). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). Computational tools for this variant suggests no significant impact on splicing and does not affect the protein function (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.00) (BP4). To our knowledge, functional studies have been reported for this variant. Co-occurrences with a pathogenic variant has been reported (MLH1 c.1989G>A; Lagerstedt-Robinson 2016). MSH6 c.773T>C has also been reported in a FAP individual (Kim 2019). It has been reported as an uncertain significance in ClinVar. Based on the currently available information, c.773T>C is classified as an uncertain significance variant according to MMR specif. draft v3.1. -

Nov 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with threonine at codon 258 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.773T>C (p.Ile258Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251164 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.773T>C has been reported in the literature in individuals affected with Lynch Syndrome or FAP (Lagerstedt-Robinson_2016, Kim_2019). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with a pathogenic variant has been reported (MLH1 c.1989G>A; Lagerstedt-Robinson_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Lynch syndrome Uncertain:1

Apr 27, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 258 of the MSH6 protein (p.Ile258Thr). 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 (PMID: 34897210). ClinVar contains an entry for this variant (Variation ID: 491992). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.0099	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Benign	0.80
DEOGEN2	Benign	0.22	.;T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.8	.;L;.
PhyloP100		0.22
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.42	N;N;.
REVEL	Benign	0.18
Sift	Benign	0.69	T;T;.
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.25
MutPred		0.24		.;Gain of relative solvent accessibility (P = 0.0023);.;
MVP		0.57
ClinPred		0.062	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.099
Mutation Taster		=29/71	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: rs1553412195; hg19: chr2-48025895; COSMIC: COSV52288450;