rs587782858

Positions:

• chr2-47800536-CAAG-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_000179.3(MSH6):​c.2561_2563del​(p.Lys854del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,613,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: MSH6 NM_000179.3 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:11
• Conservation: PhyloP100: 9.26

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: Nonframeshift variant in NON repetitive region in NM_000179.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.2561_2563del	p.Lys854del	inframe_deletion	4/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.2561_2563del	p.Lys854del	inframe_deletion	4/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249108 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135170

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461252 Hom.: 0 AF XY: 0.0000248 AC XY: 18 AN XY: 726958

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74230

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 19, 2023	The c.2561_2563delAGA variant (also known as p.K854del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame AGA deletion at nucleotide positions 2561 to 2563, causing the removal of a lysine residue at codon 854. This alteration has been reported in a French patient with a clinical diagnosis of Constitutional Mismatch Repair Deficiency (CMMRD) syndrome in conjunction with a known MSH6 pathogenic mutation; however, authors note that the clinical presentation is more consistent with an early form of Lynch syndrome than with CMMRD, suggesting that this alteration may not be completely inactivating (Bougeard G et al. Fam. Cancer. 2014 Mar;13:131-5; Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8). This alteration was also detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration has also been identified in several individuals with Lynch-associated tumors that were microsatellite stable (MSS) and/or had normal mismatch repair protein expression on immunohistochemistry (IHC) (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 10, 2022	This variant causes a deletion of 1 amino acid from the MSH6 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in trans with a pathogenic frameshift mutation in an individual affected with early-onset Lynch syndrome (PMID: 24068316, 26318770). This variant has also been observed as a somatic variant in a tumor sample from in an individual affected with Lynch syndrome, who carried a pathogenic MSH2 mutation (inversion of exons 1 - 7 inversion, also known as Boland mutation) in the germline (PMID: 29755653). This variant has been identified in 5/249108 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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2023	Variant summary: MSH6 c.2561_2563delAGA (p.Lys854del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 249108 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2561_2563delAGA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer or breast cancer (Bougeard_2014, Gray_2018, Hampel_2018, Nikitin_2020, Salvador_2018, Tung_2014, Lin_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant has been reported in a patient with Constitutional Mismatch Repair-Deficiency Syndrome (MSH6 c.3261dupC, p.Phe1088Leufs*5), providing supporting evidence for a benign role (Bodo_2015). 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: 26116798, 24068316, 29755653, 29596542, 35752529, 32547938, 30702970, 25186627). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 15, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2023	In-frame deletion of 1 amino acid in a non-repeat region; Observed with a pathogenic MSH6 variant on the opposite allele (in trans) in a case of possible constitutional mismatch repair deficiency (CMMR-D), but analysis of all mismatch repair genes was not performed and therefore this variant may not be responsible for the phenotype (Bougeard et al., 2014); Observed in individuals with breast cancer (Tung et al., 2015; Nikitin et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Located in the critical Lever domain (Warren et al., 2007; Kansikas et al., 2011); This variant is associated with the following publications: (PMID: 29596542, 30877237, 26318770, 26116798, 29755653, 17531815, 21120944, 30702970, 32547938, 35752529, 25186627, 24068316) -

Lynch-like syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Constitutional Genetics Lab, Leon Berard Cancer Center

Jul 01, 2019

- -

Lynch syndrome 5 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Oct 09, 2023

- -

MSH6-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2024

The MSH6 c.2561_2563delAGA variant is predicted to result in an in-frame deletion (p.Lys854del). This variant was reported in several individuals with clinical features of Lynch syndrome or constitutional mismatch repair deficiency syndrome (Bougeard et al. 2014. PubMed ID: 24068316; Jensson et al. 2023. PubMed ID: 37937776; Tung et al. 2014. PubMed ID: 25186627; Salvador et al. 2019. PubMed ID: 30702970). This variant is reported in 0.0036% of alleles in individuals of European (non-Finnish) descent in gnomAD and is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142970/). Although we suspect this variant may be pathogenic, at this time the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This variant, c.2561_2563del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Lys854del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs751683437, gnomAD 0.004%). This variant has been observed in individual(s) with constitutional mismatch repair deficiency syndrome and breast cancer and clinical features of Lynch syndrome (PMID: 25186627, 26318770, 32547938; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 142970). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Mar 25, 2024

- -

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: rs587782858; hg19: chr2-48027675;