NM_000179.3:c.3601C>G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000179.3(MSH6):c.3601C>G(p.Leu1201Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,612,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4

Conservation

PhyloP100: 4.56

Variant links:

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]

MSH6 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 2-47805662-C-G is Pathogenic according to our data. Variant chr2-47805662-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89423.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.3601C>G	p.Leu1201Val	missense_variant	Exon 7 of 10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.3601C>G	p.Leu1201Val	missense_variant	Exon 7 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151754

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461158

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726912

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151754

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74076

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Jun 02, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with valine at codon 1201 in the ATPase domain of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported to be in complete linkage disequilibrium with c.3724C>A (p.Arg1242Ser) (ClinVar SCV000276654.6). This haplotype has been observed in multiple individuals affected with Lynch syndrome-associated cancers (PMID: 29875428, 31391288, 34994648; O'Leary 2014; ClinVar variation ID: 89423), and in an individual affected with constitutional mismatch repair deficiency who carried a pathogenic MSH6 c.3434-2A>G variant on the different chromosome (Alshuaibi et al., ACMG 2016 poster). The p.Leu1201Val variant has been identified in 1/31336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). It remains a possibility that p.Arg1242Ser and p.Leu1201Val variants in cis may act in synergy to adversely affect MSH6 protein function. However, different missense variants that alter arginine at codon 1242 (p.Arg1242His and p.Arg1242del) are known to be disease-causing, indicating the functional and clinical importance of arginine at this position (ClinVar variation ID: 140866 and 89450). Based on the available evidence, we conclude that the phenotype observed in individuals carrying the double mutant allele may be attributable to the p.Arg1242Ser variant, while the role of p.Leu1201Val variant in disease remains unclear. Therefore, this p.Leu1201Val variant is classified as a Variant of Uncertain Significance. -

Aug 27, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L1201V variant (also known as c.3601C>G), located in coding exon 7 of the MSH6 gene, results from a C to G substitution at nucleotide position 3601. The leucine at codon 1201 is replaced by valine, an amino acid with highly similar properties. The p.R1242S variant (also known as c.3724C>A), located in coding exon 8 of the MSH6 gene, results from a C to A substitution at nucleotide position 3724. The arginine at codon 1242 is replaced by serine, an amino acid with dissimilar properties. The p.L1201V and p.R1242S alterations have been observed to be linked in cis and in complete linkage disequilibrium (Ambry internal data). This haplotype has been observed in several individuals diagnosed with Lynch-related tumors in their 40-50s, including individuals who met Amsterdam criteria and with MSI-H colorectal tumors and/or loss of MSH6 on immunohistochemistry (O'Leary et al. Am. J. Digest. Dis. 2014;1(1):62-66; Ambry internal data). This haplotype has also been observed in conjunction with a mutation in MSH6 (c.3439-2A>G) in a girl with clinical features consistent with constitutional mismatch repair deficiency (CMMRD) syndrome (external laboratory communication).This haplotype was also detected in a pediatric patient with high-grade glioma (Crotty EE et al. J Neurooncol, 2020 Jul;148:607-617). Based on internal structural analysis, this haplotype is more destabilizing than known likely pathogenic variants in the same domain. This amino acid position is highly conserved in available vertebrate species. The in silico predictions for p.L1201V and p.R1242S alterations are inconclusive and deleterious, respectively. Based on the majority of available evidence to date, this haplotype is likely to be pathogenic. -

not provided

Uncertain:2

Aug 01, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 22, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: none, 29875428) -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1201 of the MSH6 protein (p.Leu1201Val). This variant is present in population databases (rs182024561, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of Lynch syndrome, and has been frequently observed in cis with MSH6 c.3724C>A (p.Arg1242Ser) (PMID: 29875428; internal data). ClinVar contains an entry for this variant (Variation ID: 89423). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MSH6 function with a negative predictive value of 95%. 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. -

Endometrial carcinoma

Pathogenic:1

Feb 21, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

May 07, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu1201Val variant in MSH6 has been reported in 2 individuals with colorectal cancer (O'Leary 2014, Turner 2018). It has also been identified in 1/15396 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Uncertain significance on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89423). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

.;.;T;D;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

.;D;D;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

1.9

.;.;.;M;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.9

.;D;.;D;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

.;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

.;.;.;D;.

Vest4

0.86

MutPred

0.75

.;.;.;Gain of catalytic residue at L1201 (P = 0.0194);.;

MVP

0.97

ClinPred

0.98

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.91

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over