2-47799278-T-C

Variant names:

• chr2-47799278-T-C
• rs750528093
• NM_000179.3:c.1295T>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.1295T>C​(p.Phe432Ser) 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. 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. F432C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.81
• Publications: 9 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 3 benign, 40 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 chr2-47799278-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 649648.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 2-47799278-T-C is Pathogenic according to our data. Variant chr2-47799278-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.1295T>C	p.Phe432Ser	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.1295T>C	p.Phe432Ser	missense_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Mar 21, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: defective mismatch repair activity (PMID: 31965077); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17531815, 28152038, 24933100, 28765196, 30217226, 30212499, 30787465, 21120944, 35884469, 31844177, 31965077) -

May 21, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, the variant has been reported in individuals with colorectal cancer and/or endometrial cancer (PMID: 28765196 (2017), 24933100 (2014)). A functional study indicated the variant caused impaired DNA mismatch binding and severely deficient MMR activity in vitro (PMID 31965077 (2020)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 11, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F432S pathogenic mutation (also known as c.1295T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1295. The phenylalanine at codon 432 is replaced by serine, an amino acid with highly dissimilar properties. This alteration has been observed in multiple individuals with Lynch syndrome-associated cancers and families that meet Amsterdam criteria including an individual with clinical features consistent with constitutional mismatch repair deficiency syndrome (CMMRD) (Nassar AH et al. Genet Med, 2020 Apr;22:709-718; Kim YN et al. Cancers (Basel), 2022 Jul;14; Ambry internal data). This alteration was reported in an individual diagnosed with endometrial cancer whose tumor demonstrated low microsatellite instability and normal MSH6 expression on immunohistochemistry (IHC) (Batte BA et al. Gynecol. Oncol., 2014 Aug;134:319-25; Borras E et al. Cancer Prev Res (Phila), 2017 Oct;10:580-587). This alteration has been reported as functionally defective based on results from a complementation assay performed in mammalian cells (Drost M et al. Genet. Med., 2020 May;22:847-856). Another alteration at the same codon, p.F432A, was shown to have reduced DNA binding and abolished mismatch repair activity in an in vitro functional assay (Dufner P et al. J. Biol. Chem., 2000 Nov;275:36550-5). Based on internal structural analysis using published crystal structures, this alteration is important to protein function and moderately destabilizing to the local structure (Warren JJ et al. Mol. Cell, 2007 May;26:579-92; Sharma M et al. Biophys. J., 2014 Jun;106:2483-92; Reyes GX et al. Chromosoma, 2015 Dec;124:443-62). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Nov 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces phenylalanine with serine at codon 432 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This substitution disrupts a conserved Phe-X-Glu motif that contacts mis-paired DNA bases (PMID: 17531815). A functional study has shown that this variant impacts MMR function in vitro and the equivalent variant in the mouse Msh6 homolog also disrupts DNA mismatch binding and Msh6 function in a genetic screen for tolerance to 6-thioguanine (PMID: 31965077). This variant has been observed in individuals affected with Lynch syndrome-associated cancer (PMID: 24933100, 28765196, 35884469). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Endometrial carcinoma Pathogenic:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Phe432Ser variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, ClinVar database, or UMD. The p.Phe432 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD, BLOSUM) suggest that the p.Phe432Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Functional studies using site-directed mutagenesis have shown that a different alteration at this position, a substitution of phenylalanine for alanine at residue 432, abolished not only mismatch recognition but also the binding of the MSH2-MSH6 complex to DNA in general (Drotschmann 2001, Dufner 2000, Dalhus 2009), increasing the likelihood that the mutations at this highly conserved residue are of clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic. -

Jun 20, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 5 Pathogenic:1

Aug 11, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 31965077]. This variant is expected to disrupt protein structure [Myriad internal data]. -

not specified Pathogenic:1

May 01, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

PS3, PS4_mod, PM2_sup, PP4 -

Hereditary nonpolyposis colon cancer Pathogenic:1

Mar 13, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.1295T>C (p.Phe432Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251280 control chromosomes. c.1295T>C has been reported in the literature in individuals affected with HNPCC-associated cancers (Batte_2014, Borras_2017, Kim_2022). These data indicate that the variant may be associated with disease. The variant was reported as damaging via the complete in vitro MMR activity (CIMRA) assay used to quantify the functional activity of variants in MMR genes (Drost_2020). The following publications have been ascertained in the context of this evaluation (PMID: 24933100, 28765196, 11641390, 10938287, 35884469, 31965077). ClinVar contains an entry for this variant (Variation ID: 183760). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Lynch syndrome Pathogenic:1

May 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces phenylalanine with serine at codon 432 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This substitution disrupts a conserved Phe-X-Glu motif that contacts mis-paired DNA bases (PMID: 17531815). A functional study has shown that this variant impacts MMR function in vitro and the equivalent variant in the mouse Msh6 homolog also disrupts DNA mismatch binding and Msh6 function in a genetic screen for tolerance to 6-thioguanine (PMID: 31965077). This variant has been observed in individuals affected with Lynch syndrome-associated cancer (PMID: 24933100, 28765196, 35884469). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 432 of the MSH6 protein (p.Phe432Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MSH6-related conditions (PMID: 24933100, 28765196). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. ClinVar contains an entry for this variant (Variation ID: 183760). 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%. Experimental studies have shown that this missense change affects MSH6 function (PMID: 31965077). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;.;D;D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	.;.;H;.;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.9	.;D;D;.;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	.;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.98
MutPred		0.89		.;.;Gain of sheet (P = 0.0827);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.89
Mutation Taster		=1/99	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: rs750528093; hg19: chr2-48026417;