rs1553334056

chr2-47806836-G-GCTGA

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4 BS1_Supporting

The NM_000179.3(MSH6):c.4062_4065dup(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. L1353L) 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:5 B:1
• Conservation: PhyloP100: 0.00300

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 Uncertain_significance. Variant got 1 ACMG points.

• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1385 codons.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome 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 gnomad4_exome. There are 41 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.4062_4065dup	p.Leu1356AspfsTer4	frameshift_variant	10/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.4062_4065dup	p.Leu1356AspfsTer4	frameshift_variant	10/10	1	NM_000179.3	P4

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

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 250986 Hom.: 0 AF XY: 0.0000958 AC XY: 13 AN XY: 135646

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 SAS exome AF: 0.000426

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000488

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000629

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 25, 2023	The c.4062_4065dupGACT variant is located in coding exon 10 of the MSH6 gene and results from a duplication of GACT at positions 4062-4065 causing a translational frameshift with a predicted alternate stop codon (p.L1356Dfs*4). This variant has been identified in probands whose Lynch syndrome-associated tumors were microsatellite stable (MSS) and/or demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC) (Ambry internal data; Kraus C et al. Int. J. Cancer. 2015 Mar;136:E559-68). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of MSH6, is not expected to trigger nonsense-mediated mRNA decay, and results in alteration of three amino acids and removal of the last two amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, another alteration leading to premature truncation at the same position has been reported at high frequency in the Chinese population and is considered a benign polymorphism (Chan TL et al. J. Natl. Cancer Inst. 1999 Jul;91:1221-6). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 06, 2023	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), breast cancer (PMID: 31784482; doi: 10.1016/j.gim.2022.01.077), 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. -

Lynch syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

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 (Invitae). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 26, 2023

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 20, 2019

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), but is predicted to result in a mutant protein that replaces the last 5 amino acids. 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. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Though the variant, c.4062_4065dupGACT, has been reported in the literature in two affected individuals (Kraus_2015, Borras_2017), in one of these cases a microsatellite stable tumor was noted (Kraus_2015), and in the other patient a co-occurring likely pathogenic MLH1 variant (c.306G>T, p.E102D) was reported (Borras_2017). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

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: rs1553334056; hg19: chr2-48033975;