rs63750119

Positions:

• chr2-47806282-G-A
• chr2-47806282-G-C
• chr2-47806282-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000179.3(MSH6):​c.3725G>A​(p.Arg1242His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 9.49

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 2-47806282-G-A is Pathogenic according to our data. Variant chr2-47806282-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47806282-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3725G>A	p.Arg1242His	missense_variant	8/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3725G>A	p.Arg1242His	missense_variant	8/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251180 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461686 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 28, 2022	The frequency of this variant in the general population, 0.000004 (1/251180 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 35014770 (2022)) and in several individuals who were referred for hereditary cancer testing (PMID: 24763289, 28514183). It was also reported as a homozygous variant in 2 siblings affected with high grade gliomas in the published literature (PMID: 32642664 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 30, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 26, 2018	The c.3725G>A; p.Arg1242His variant (rs63750119) has been described in the homozygous state in two brothers with gliomas, one of whom also had cafe-au-lait macules (see link for UMD database, Grandval 2013). This variant is reported as likely pathogenic by multiple laboratories in ClinVar (Variation ID: 140866) and is observed in only 1 out of 245952 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 1242 is highly conserved within domain V of the MutS domain (Warren 2007) and computational algorithms (PolyPhen-2, SIFT) predict this variant to be deleterious. Additionally, another variant at this codon (p.Arg1242Ser) has been reported in individuals with colorectal cancer (O’Leary 2014). Based on available information, this variant is considered likely pathogenic. References: Link to UMD database: http://139.124.156.133/4D_molecules/UMD175743.html Grandval P et al. UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families. O’Leary E et al. A multi-disciplinary cancer program enhances hereditary colorectal cancer detection. Am J Digest Dis 2014;1(1):62-66. Warren J et al. Structure of the human MutSalpha DNA lesion recognition complex. Mol Cell. 2007;26:579–592. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2024	Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene referred for genetic testing at Genedx and in the published literature (PMID: 24763289); 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: 25370038, 17531815, 25111426, 29596542, 21120944, 23729658, 30787465, 31391288, 29922827, 31204389, 30128536, 29915797, 28514183, 17718861, 38175816, 35014770, 36425062, 37319387, 24763289, 32642664) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Likely pathogenic and reported on 10/26/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Lynch syndrome 5 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 16, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 29, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 32642664]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 07, 2023	The p.R1242H pathogenic mutation (also known as c.3725G>A), located in coding exon 8 of the MSH6 gene, results from a G to A substitution at nucleotide position 3725. The arginine at codon 1242 is replaced by histidine, an amino acid with highly similar properties. This mutation was detected in trans with a pathogenic MSH6 mutation in an individual whose clinical presentation was consistent with CMMR-D, with isolated absence of MSH6 in both tumor and normal tissue by immunohistochemistry (IHC; LaDuca H et al. Genet. Med. 2014;16(11):830-7). This pathogenic mutation has also been reported as a homozygous, germline finding in two siblings diagnosed with a high grade glioma in childhood (Guerrini-Rousseau L et al. Neurooncol Adv. Dec;1:vdz033). In addition, this mutation has been identified in multiple probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH6 expression by IHC (Ambry internal data). Based on an internal structural analysis, this mutation is anticipated to result in a significant decrease in structural stability (Warren JJ et al. Mol. Cell. 2007 May;26:579-92). An in-frame deletion of the arginine residue at codon 1242 has been detected in multiple families meeting diagnostic criteria for Lynch syndrome, supporting the pathogenicity of alterations at this position (Roncari B et al. Clin Genet. 2007 Sep;72(3):230-7; LaDuca H et al. Genet. Med. 2014 Nov; 16(11):830-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 20, 2023	This missense variant replaces arginine with histidine at codon 1242 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 in the homozygous state in two brothers affected with constitutional mismatch repair deficiency (PMID: 32642664), and in a 23 year old individual affected with colorectal cancer and polyps who carried another MSH6 pathogenic variant in trans (LOVD database). This variant has also been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated disease (PMID: 29915797, 36425062; ClinVar SCV000183784.8; Insight database), breast cancer (PMID: 30128536), and in individuals who underwent hereditary cancer multigene panel testing (PMID: 24763289, 28514183). In addition, different variants that affect the amino acid at the same position (p.Arg1242del and p.Arg1242Ser) are considered to be disease-causing (ClinVar variation ID: 89450, 89449), suggesting that arginine at this position is important for protein structure and function. This variant has been identified in 1/251180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 28, 2020

Variant summary: MSH6 c.3725G>A (p.Arg1242His) results in a non-conservative amino acid change located in the MutS, C-terminal domain (IPR000432) of the encoded protein sequence, which is comprised of the ATPase domain and the HTH (helix-turn-helix) domain, the latter being involved in dimer contacts. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245952 control chromosomes (gnomAD). c.3725G>A has been reported in the literature in individuals affected with Lynch Syndrome (LS) (LaDuca 2014, Espenschied 2017). It was reported in two patients (brothers) in homozygosity who had symptoms characteristic of constitutive mismatch repair deficiency (CMMRD) syndrome (UMD data) and isolated lack of MSH6 staining on IHC, indicating causality. Another individual was also reported with a phenotype suggestive of CMMRD, who also carried a likely pathogenic MSH6 variant (c.3G>T (p.Met1Ile)) in trans, with the lack of MSH6 staining in the tumor as well as in normal tissue (InSiGHT data), consistent with biallelic loss of MSH6. A further patient with clinical features suggestive of CMMRD has been reported by Ambry Genetics (Dalton 2015). These data indicate that the variant is likely to be associated with disease. Of note, the variant was identified along with another co-occurring pathogenic variant in the ATM gene (c. 7271T>G (p.V2424G)) in a 27 year old female tested at our laboratory with personal and family history of Breast Cancer. However, the association of MSH6 c.3725G>A with LS remains unclear as no clinical information on two other carriers of this variant (father, sister) were available at the time of evaluation. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Lynch syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 10, 2023

This missense variant replaces arginine with histidine at codon 1242 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 in the homozygous state in two brothers affected with constitutional mismatch repair deficiency (PMID: 32642664), and in a 23 year old individual affected with colorectal cancer and polyps who carried another MSH6 pathogenic variant in trans (LOVD database). This variant has also been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated disease (PMID: 29915797, 36425062; ClinVar SCV000183784.8; Insight database), breast cancer (PMID: 30128536), and in individuals who underwent hereditary cancer multigene panel testing (PMID: 24763289, 28514183). In addition, different variant that affect the amino acid at the same position (p.Arg1242del and p.Arg1242Ser) are considered to be disease-causing (ClinVar variation ID: 89450, 89449), suggesting that arginine at this position is important for protein structure and function. This variant has been identified in 1/251180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1242 of the MSH6 protein (p.Arg1242His). This variant is present in population databases (rs63750119, gnomAD 0.006%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency and/or individuals who were referred for hereditary cancer testing (PMID: 24763289, 28514183, 31204389). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 140866). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	.;.;T;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.1	.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.8	.;D;.;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;.;D;D
Sift4G	Uncertain	0.0030	D;D;T;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.89
MutPred		0.76		.;.;.;Loss of sheet (P = 0.1158);.;
MVP		0.97
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.86

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

Other links and lift over

dbSNP: rs63750119; hg19: chr2-48033421; COSMIC: COSV52278636; COSMIC: COSV52278636;