rs1553334056

Variant names:

• chr2-47806836-G-GCTGA
• rs1553334056
• NM_000179.3:c.4062_4065dupGACT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PVS1_Moderate BS1_Supporting

The NM_000179.3(MSH6):​c.4062_4065dupGACT​(p.Leu1356AspfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,610,660 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1356L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000036 (1 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.00300
• Publications: 1 publications found

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]

FBXO11 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00416 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000363 (53/1460340) while in subpopulation SAS AF = 0.000488 (42/86064). AF 95% confidence interval is 0.00037. There are 1 homozygotes in GnomAdExome4. There are 41 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.4062_4065dupGACT	p.Leu1356AspfsTer4	frameshift_variant	Exon 10 of 10	ENST00000234420.11	NP_000170.1
FBXO11	NM_001190274.2	c.*1278_*1281dupTCAG		downstream_gene_variant		ENST00000403359.8	NP_001177203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.4062_4065dupGACT	p.Leu1356AspfsTer4	frameshift_variant	Exon 10 of 10	1	NM_000179.3	ENSP00000234420.5
FBXO11	ENST00000403359.8	c.*1278_*1281dupTCAG		downstream_gene_variant		1	NM_001190274.2	ENSP00000384823.4

Frequencies

GnomAD3 genomes AF: 0.0000200 AC: 3 AN: 150208 Hom.: 0 Cov.: 31

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: 0.000629

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 250986 AF XY: 0.0000958

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1460340 Hom.: 1 Cov.: 32 AF XY: 0.0000564 AC XY: 41 AN XY: 726490

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.0000224 AC: 1 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39644

South Asian (SAS) AF: 0.000488 AC: 42 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111070

Other (OTH) AF: 0.0000166 AC: 1 AN: 60348

GnomAD4 genome AF: 0.0000200 AC: 3 AN: 150320 Hom.: 0 Cov.: 31 AF XY: 0.0000273 AC XY: 2 AN XY: 73270

African (AFR) AF: 0.00 AC: 0 AN: 40744

American (AMR) AF: 0.00 AC: 0 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.000629 AC: 3 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67782

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Feb 25, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.4062_4065dupGACT (p.Leu1356AspfsX4) results in a frameshift, causing a premature termination codon in the last exon of the encoded protein. The variant is located 5 amino acids upstream from the termination codon, therefore it is unlikely to trigger nonsense-mediated decay (NMD). The variant allele was found at a frequency of 6.4e-05 in 250986 control chromosomes, predominantly at a frequency of 0.00043 within the South Asian subpopulation in the gnomAD database, and a homozygous individual has been reported in the gnomAD v4 database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3.027 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing autosomal dominant Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014). However, this variant frequency does not exceed the universal estimated maximal expected allele frequency for the recessive condition, Mismatch repair cancer syndrome 3 (OMIM 619097). Though the variant, c.4062_4065dupGACT, has been reported in the heterozygous state in the literature in affected individuals with breast cancer (example, Bhai_2021), prostate cancer (example, Matejcic_2020), colorectal cancer or Lynch syndrome (Kraus_2015, Borras_2017), in one of these cases a microsatellite stable tumor was noted (Kraus_2015), and in another patient a co-occurring likely pathogenic MLH1 variant (c.306G>T, p.E102D) was reported (Borras_2017). In all these cases, there was no strong evidence for variant causality. In addition, a similar frameshift variant affecting the same C-terminal amino acids (p.Leu1356Serfs*4) was also found in 11/99 Southern Chinese controls and classified as a common polymorphism (PMID 10413423). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 28765196, 25142776, 32832836). ClinVar contains an entry for this variant (Variation ID: 185259). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classification criteria: BS1, PVS1_Moderate -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Nov 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 4 nucleotides in exon 10 of the MSH6 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein, impacting the last five amino acids. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individuals affected with colorectal cancer (PMID: 25142776), prostate cancer (PMID: 32832836), and Lynch syndrome (PMID: 28765196). This variant has been identified in 16/250986 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jun 05, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Lynch syndrome Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Leu1356AspfsX4 variant was identified in 1 of 304 proband chromosomes (frequency: 0.003) from German individuals or families with CRC (Kraus 2014). The variant was also identified in dbSNP (ID: rs775836476) as “NA”, ClinVar (classified as uncertain significance by Ambry Genetics), Clinvitae (1x), and in control databases in 15 of 245802 chromosomes at a frequency of 0.00006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: South Asian in 13 of 30692 chromosomes (frequency: 0.0004), East Asian in 1 of 17226 chromosomes (frequency: 0.00006) and European Non-Finnish in 1 of 111546 chromosomes (frequency 0.000009). The variant was not identified in Genesight-COGR, Cosmic, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The p.Leu1356AspfsX4 is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1356 and leads to a premature stop codon 4 codons downstream, shortening the protein transcript by 2 amino acids. Notably, variants occurring 50 base pairs before the penultimate exon junction/in the last exon of the gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay, although further study would be required to validate this hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu1356Aspfs*4) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the MSH6 protein. This variant is present in population databases (rs775836476, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome, colorectal cancer, prostate cancer, and thyroid cancer (PMID: 25142776, 28765196, 29625052, 32832836). ClinVar contains an entry for this variant (Variation ID: 185259). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Endometrial carcinoma Uncertain:1

Oct 26, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0030
Mutation Taster		=73/127	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1553334056; hg19: chr2-48033975;