2-47806628-GAATC-GAATCAATC

Variant names:

• chr2-47806628-G-GAATC
• rs1553333738
• NM_000179.3:c.3980_3983dupATCA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000179.3(MSH6):​c.3980_3983dupATCA​(p.Leu1330ValfsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000206 in 1,459,480 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. QS1328QS?) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 4.12

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47806628-G-GAATC is Pathogenic according to our data. Variant chr2-47806628-G-GAATC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 184998.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.3980_3983dupATCA	p.Leu1330ValfsTer12	frameshift_variant	Exon 9 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3980_3983dupATCA	p.Leu1330ValfsTer12	frameshift_variant	Exon 9 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246946 Hom.: 0 AF XY: 0.00000748 AC XY: 1 AN XY: 133762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459480 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 726138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Jul 25, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Observed as homozygous in a patient with constitutional mismatch repair deficiency (CMMR-D) (Toledano et al., 2019); Observed as heterozygous in individuals with a personal or family history consistent with pathogenic variants in this gene (Baglietto et al., 2010; Yang et al., 2021); Not observed at a 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: 31730237, 28152038, 31447099, 34148862, 36988593, 32844218, 34086170, 20028993, 29922827, 32030746, 31501241, 33977078) -

Nov 06, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.3980_3983dup (p.Leu1330Valfs*12) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. This variant has been reported in the published literature in individuals affected with colon cancer and endometrial cancer (PMIDs: 38722212 (2024), 32844218 (2021)) as well as constitutional mismatch repair deficiency (CMMRD) syndrome (PMIDs: 31730237 (2020), 31501241 (2020)). Other published studies have shown that this variant has deleterious effects on the expression and function of the MSH6 protein (PMIDs: 22250089 (2012), 32844218 (2021)). The frequency of this variant in the general population, 0.000004 (1/246946 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Lynch syndrome 5 Pathogenic:2

Aug 28, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 06, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Oct 08, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3980_3983dupATCA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of ATCA at nucleotide positions 3980 to 3983, causing a translational frameshift with a predicted alternate stop codon (p.L1330Vfs*12). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 2.3% of the protein. However, premature stop codons are typically deleterious in nature. This mutation was identified once in a pool of Scottish probands with either colon or endometrial cancer diagnosed before age 55 (Baglietto L et al. J Natl Cancer Inst. 2010 Feb 3;102(3):193-201) and in individuals meeting Amsterdam criteria (Ambry internal data). In addition, this mutation was reported as homozygous in an individual with constitutional mismatch repair deficiency (CMMRD) (Shapira Rootman M et al. Clin Genet, 2020 02;97:296-304). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Jan 15, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 4 nucleotides in exon 9 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 1/246946 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. -

Carcinoma of colon Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Leu1330ValfsX12 variant was identified in 3 of 69962 proband chromosomes (frequency: 0.00004) from individuals or families with lynch syndrome (Espenschied 2017). The variant was also identified in dbSNP (ID: rs786204180) as N/A, ClinVar (classified as pathogenic by Ambry Genetics, Invitae, GenDxl; classified as likely pathogenic by Mayo Clinic), Clinvitae (classified as pathogenic by ClinVar and Invitae), databases. The variant was not identified in UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.3980_3983dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1330 and leads to a premature stop codon at position 1341. This alteration is then predicted to result in 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. -

Hereditary nonpolyposis colon cancer Pathogenic:1

May 01, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.3980_3983dupATCA (p.Leu1330ValfsX12) 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. The variant allele was found at a frequency of 4e-06 in 246946 control chromosomes. c.3980_3983dupATCA has been reported in the literature in multiple individuals affected with Lynch syndrome and features of CMMRD (constitutional mismatch repair deficiency) (example, Baglietto_2010, Gardes_2012, Epsenschied_2017, Toledano_2019, Rootman_2020, Dong_2020). These data indicate that the variant is very likely to be associated with disease. 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome Pathogenic:1

Oct 27, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu1330fs (c.3984_3987dupATCA) variant in MSH6 has been reported in at least 1 individual with Lynch syndrome-associated cancers (Baglietto 2010 PMID: 20028993) and in homozygous state in 1 individual with constitutional mismatch repair deficiency syndrome (CMMRD; Shapira Rootman 2020 PMID: 31730237, Toledano 2020 PMID: 31501241). Additionally, another variant at this position (c.3984_3987dupGTCA) leading to the same frameshift has been described as an Ashkenazi Jewish founder variant and has been shown to cause loss of expression of MSH6 protein (Goldberg 2010 PMID: 19851887). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 184998) and has been identified in 1/111536 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1330 and leads to a premature termination codon 12 amino acids downstream. Although this termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD), the available evidence from the other Ashkenazi Jewish founder variant shows that the variant ultimately leads to loss of function. 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 Lynch syndrome in an autosomal dominant manner based upon the predicted impact to the protein and the presence of an established pathogenic variant with the same amino acid change. ACMG/AMP Criteria applied: PS1; PVS1_Strong, PM2_Supporting. -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu1330Valfs*12) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the MSH6 protein. This variant is present in population databases (rs786204180, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of MSH6-related conditions (PMID: 14520694, 19851887, 20028993, 24440087). 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: 184998). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Jun 21, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553333738; hg19: chr2-48033767;