2-47801086-C-T

Position:

• chr2-47801086-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000179.3(MSH6):​c.3103C>T​(p.Arg1035*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,458,740 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 Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MSH6 NM_000179.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:24
• Conservation: PhyloP100: 3.33

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]

MSH6 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-47801086-C-T is Pathogenic according to our data. Variant chr2-47801086-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 89338.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47801086-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3103C>T	p.Arg1035*	stop_gained	4/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3103C>T	p.Arg1035*	stop_gained	4/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247790 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 133974

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1458740 Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9 AN XY: 725516

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 12362848, 15236168, 10471527, 18269114, 25525159, 22658618, 23047549, 18301448, 15483016, 26720728, 24728189, 22006311, 25006859, 32980694, 31830689, 29922827, 27863258, 27372833, 29489754, 32660107, 30719162, 31307542, 32719484, 30787465, 30147880) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 05, 2022	PP4, PP5, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 25, 2022	This nonsense variant causes the premature termination of MSH6 protein synthesis. The frequency of this variant in the general population, 0.000012 (3/247790 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021)), colorectal cancer (PMID: 27372833 (2016)), ovarian cancer (PMID: 26720728 (2016), 23047549 (2012), 22006311 (2011)), and endometrial cancer (PMID: 18301448 (2008), 18269114 (2004), 15236168 (2004), 10471527 (1999)). In addition, the variant has been detected in an individual with constitutional mismatch repair deficiency (CMMRD) syndrome who was compound heterozygous for the variant and a pathogenic MSH6 variant (PMID: 30147880 (2018)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 10, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 03, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 30, 2023	- -

Lynch syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 09, 2024	The c.3103C>T variant in the MSH6 gene is located on the exon 4 and introduces a premature translation termination codon (p.Arg1035*), resulting in an absent or disrupted protein product. This variant has been reported in multiple unrelated individuals with Lynch syndrome-associated cancer (PMID: 34667028, 25006859, 31307542, 27601186, 18269114, 27372833, 15483016). Loss-of-function variants of MSH6 are known to be pathogenic (PMID: 30376427, 18269114, 29345684). The variant is reported in ClinVar as pathogenic (ID: 89338) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (3/247790 chromosomes). Therefore, the c.3103C>T (p.Arg1035*) variant in the MSH6 gene has been classified as pathogenic. -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Arg1035X variant in MSH6 has been previously reported in 1 individual with consitutive mismatch repair deficiency syndrome (compound heterozygous), 1 individual with pediatric CNS tumor, 1 individual with ovarian cancer and 6 individuals with endometrial cancer (1 of whom also carried a nonsense variant in BRIP1), and segregatted with disease in 2 affected relatives from 2 families (Pal 2102, Norquist 2016, Planck 1999, Hendriks 2004, Devlin 2008, Planschke 2004, Ling 2018, Grobner 2018). It has also been identified in 1/18338 of East Asian and 2/112342 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89338). This nonsense variant leads to a premature termination codon at position 1035, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_Moderate, PM3. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 22, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 05, 2021	The c.3103C>T variant in the MSH6 gene is located on the exon 4 and introduces a premature translation termination codon (p.Arg1035*), resulting in an absent or disrupted protein product. This variant has been reported in multiple unrelated individuals with Lynch syndrome-associated cancer (PMID: 34667028, 25006859, 31307542, 27601186, 18269114, 27372833, 15483016). Loss-of-function variants of MSH6 are known to be pathogenic (PMID: 30376427, 18269114, 29345684). The variant is reported in ClinVar as pathogenic (ID: 89338) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (3/247790 chromosomes). Therefore, the c.3103C>T (p.Arg1035*) variant in the MSH6 gene has been classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 21, 2022	The p.R1035* pathogenic mutation (also known as c.3103C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 3103. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been detected in multiple individuals diagnosed with endometrial cancer whose family histories were suspicious for Lynch syndrome (Planck M et al. Int. J. Cancer 1999 Oct;83(2):197-202; Hendriks YM et al. Gastroenterology 2004 Jul;127(1):17-25; Devlin LA et al. Ulster Med. J. 2008 Jan;77(1):25-30). This mutation was also reported in an individual diagnosed with colon cancer with a tumor exhibiting high microsatellite instability and absent MSH6 expression on IHC (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108(44):18032-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 27, 2023	This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome-associated cancers (PMID: 10471527, 15236168, 15483016, 18269114, 18301448, 22006311, 25006859, 26720728, 27601186). This variant has been identified in 3/247790 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Endometrial carcinoma Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH6 p.Arg1035X variant was identified in 4 of 816 proband chromosomes (frequency: 0.005) from individuals or families with Lynch Syndrome, and was not identified in 38 control chromosomes from healthy individuals (Everett 2014, Hendriks 2004, Pritchard 2012). The variant was identified in dbSNP (ID: rs63749999) as “With Pathogenic Allele”, in Clinvitae and Clinvar databases (pathogenic by InSIGHT, Invitae and Ambry Genetics), in COSMIC (1x with confirmed somatic status) and in InSiGHT Colon Cancer Gene Variant Database (2x as class 5 pathogenic). In addition, the variant was identified the Exome Aggregation Consortium database (August 8th 2016) in 1 of 119020 chromosomes (freq. 0.000008) in the European (Non-Finnish) population but not seen in the African, East Asian, Finnish, Latino, and South Asian populations and in the genome Aggregation Database (beta, October 19th 2016) in 2 of 242594 chromosomes (freq. 0.000008). The variant was not identified in Mismatch Repair Genes Variant, MMR Gene Unclassified Variants, Zhejiang Colon Cancer (LOVD), GeneInsight - COGR database, UMD, the 1000 Genomes and the NHLBI GO Exome Sequencing Projects databases. The p.Arg1035X variant leads to a premature stop codon at position 1035, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 03, 2024	- -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 04, 2022

- -

Lynch syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 22, 2023

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 16, 2019

Variant summary: MSH6 c.3103C>T (p.Arg1035X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 247790 control chromosomes (gnomAD). c.3103C>T has been reported in the literature in multiple individuals with personal and family history of HNPCC-associated tumors (most commonly endometrial and/or ovarian cancer) and with loss of MSH6 protein expression and microsatellite instability identified in tumor samples (e.g. Devlin_2008, Hendriks_2004, Pal_2012, Planck_1999, Plasche_2004). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change creates a premature translational stop signal (p.Arg1035*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in population databases (rs63749999, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with clinical features of Lynch syndrome (PMID: 15236168, 15483016, 22006311, 23047549). ClinVar contains an entry for this variant (Variation ID: 89338). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.93
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63749999; hg19: chr2-48028225; COSMIC: COSV52277143; COSMIC: COSV52277143;