rs1057517764

chr2-47805628-A-AT

Variant summary

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

The NM_000179.3(MSH6):c.3573dup(p.Val1192CysfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,610,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T1189T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.51

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-47805628-A-AT is Pathogenic according to our data. Variant chr2-47805628-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 372414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3573dup	p.Val1192CysfsTer2	frameshift_variant	7/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3573dup	p.Val1192CysfsTer2	frameshift_variant	7/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151744 Hom.: 0 Cov.: 33

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: 0.00000411 AC: 6 AN: 1459146 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726062

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: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151744 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74090

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

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 24, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 24, 2021	- -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2018	This duplication of one nucleotide in MSH6 is denoted c.3573dupT at the cDNA level and p.Val1192CysfsX2 (V1192CfsX2) at the protein level. The normal sequence, with the base that is duplicated in braces, is ATTTTT[T]GTTG. The duplication causes a frameshift, which changes a Valine to a Cysteine at codon 1192 and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.3573dupT has been observed in one individual with endometrial cancer demonstrating absence of MSH6 protein on immunohistochemistry whose family met revised Bethesda Criteria guidelines, as well as in one individual from a multiple colorectal cancer or Lynch syndrome family (Baglietto 2010, Buchanan 2014). We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 03, 2022	This variant inserts 1 nucleotide in exon 7 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/245904 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 28, 2021	The c.3573dupT pathogenic mutation, located in coding exon 7 of the MSH6 gene, results from a duplication of T at nucleotide position 3573, causing a translational frameshift with a predicted alternate stop codon (p.V1192Cfs*2). This mutation has been reported in multiple families with Lynch syndrome (Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201; Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31; Kwong A et al. J Mol Diagn, 2020 04;22:544-554; Brand RE et al. Fam Cancer, 2020 04;19:169-175), including a patient with MSH6-deficient endometrial cancer (Buchanan DD et al. J. Clin. Oncol. 2014 Jan;32(2):90-100) and a colorectal cancer patient with concordant IHC results (Latham A et al. J Clin Oncol, 2019 02;37:286-295). This mutation is also designated as c.3572-3573insT in published literature. 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. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The c.3573dup OR p.Val1192Cys_fsX2 variant has been reported in 1 proband with a Lynch syncrome related cancer (Baglietto_2009_20028993). The p.Val1192Cys_fsX2 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1192 and leads to a premature stop codon 2 codons downstream. This alteration is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants are an established mechanism of disease for the MSH6 gene. In summary, based upon the above information, this variant meets are criteria for pathogenicity. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 02, 2019

Variant summary: MSH6 c.3573dupT (p.Val1192CysfsX2) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3609_3612delTGCA (p.His1203fsX12), c.3699_3702delAGAA (p.Lys1233fsX6), and c.3799_3800delAT (p.Met1267fsX7)). The variant was absent in 250974 control chromosomes (gnomAD). The variant, c.3573dupT, has been reported in the literature in at least one individual affected with endometrial cancer, with the absence of MSH6 protein expression in the tumor tissue (Baglietto 2010, Buchanan_2014, Sjursen_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 03, 2023

The c.3573dup (p.Val1192Cysfs*2) variant in the MSH6 gene is located on the exon 7 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Val1192Cysfs*2), resulting in an absent or disrupted protein product. The variant has been reported in multiple unrelated individuals affected with Lynch syndrome-associated cancers (PMID: 32068069, 29368341, 27064304, 30376427, 24323032, 32459922). Loss-of-function variants located downstream to this position have been reported in individuals with Lynch syndrome (PMID: 20028993). The variant is reported in ClinVar as pathogenic (ID: 372414). This variant is absent in the general population database (gnomAD). Therefore, the c.3573dup (p.Val1192Cysfs*2) variant of MSH6 has been classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 14, 2023

ClinVar contains an entry for this variant (Variation ID: 372414). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Val1192Cysfs*2) 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 (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with endometrial cancer and Lynch syndrome (PMID: 24323032, 27064304). -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs1057517764; hg19: chr2-48032767;