chr2-47800536-CAAG-C

Variant names:

Variant summary

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

The NM_000179.3(MSH6):c.2561_2563delAGA(p.Lys854del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:11

Conservation

PhyloP100: 9.26

Variant links:

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]

MSH6 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.2561_2563delAGA	p.Lys854del	disruptive_inframe_deletion	Exon 4 of 10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.2561_2563delAGA	p.Lys854del	disruptive_inframe_deletion	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152000

Hom.:

Cov.:

show subpopulations

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:

AN:

249108

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135170

show subpopulations

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:

AN:

1461252

Hom.:

AF XY:

0.0000248

AC XY:

AN XY:

726958

show subpopulations

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:

AN:

152000

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74230

show subpopulations

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:1Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Dec 15, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 10, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Sep 11, 2023

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.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. -

not provided

Uncertain:2

Jun 17, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.2561_2563del (p.Lys854del) variant has been reported in the published literature in trans with a pathogenic MSH6 variant in an individual with suspected constitutional mismatch repair deficiency (CMMRD), however inconsistencies in tumor features and clinical presentation led to reported classification of p.Lys854del as a variant of uncertain significance in this context (PMID: 26318770 (2015), 26116798 (2015), 24068316 (2014)). This variant has also been reported in an individual with breast cancer (PMID: 25186627 (2015)). The frequency of this variant in the general population, 0.000036 (4/112662 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

Sep 23, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 01, 2019

Constitutional Genetics Lab, Leon Berard Cancer Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 5

Uncertain:1

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

MSH6-related disorder

Uncertain:1

Sep 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 benign with a negative predictive value of at least 95%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. 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

Mar 25, 2024

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over