rs267608073

Positions:

• chr2-47801019-AAAG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The ENST00000234420.11(MSH6):​c.3040_3042del​(p.Lys1014del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000657 in 152,198 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MSH6 ENST00000234420.11 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:1
• Conservation: PhyloP100: 5.67

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000234420.11. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-47801019-AAAG-A is Pathogenic according to our data. Variant chr2-47801019-AAAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 89333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3040_3042del	p.Lys1014del	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.3040_3042del	p.Lys1014del	inframe_deletion	4/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000454 AC: 1 AN: 220392 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 118232

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: 0.00000968

Gnomad OTH exome AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2024	In-frame deletion of 1 amino acid(s) in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Observed in individuals with personal or family history of HNPCC-related cancers referred for genetic testing at GeneDx and in published literature, including some with tumor studies consistent with pathogenic variants in this gene (PMID: 12658575, 18301448, 29875428); Also known as c.3037_3039delAAG, p.Lys1013del, c.3403del3, and 1013delCTT; This variant is associated with the following publications: (PMID: 12658575, 18301448, 26483394, 29875428, 32002723, 32123317, 17531815, 21120944) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 03, 2023	The frequency of this variant in the general population, 0.0000045 (1/220392 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with colorectal cancer (PMIDs: 12658575 (2003), 18301448 (2008)), uterine cancer (PMID: 29875428 (2018)), pancreatic cancer (PMID: 26483394 (2015)), an undescribed Lynch syndrome-associated cancer (PMID: 32002723 (2020)), as well as affected internal patients. Based on the available information, this variant is classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 16, 2024	The c.3040_3042delAAG variant (also known as p.K1014del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame AAG deletion between nucleotide positions 3040 and 3042, resulting in the deletion of the amino acid lysine at codon 1014. This alteration has been identified in several individuals whose hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch associated tumors displayed high microsatellite instability (MSI-H) and/or isolated loss of MSH6 expression by immunohistochemistry (IHC) (Ambry internal data). This alteration has also been reported in individuals and families with HNPCC/Lynch associated cancers including one individual with pancreatic cancer (Hu C, et al. Cancer Epidemiol. Biomarkers Prev. 2015 Oct; Wagner A, et al. Am. J. Hum. Genet. 2003 May; 72(5):1088-100; Turner SA et al. Genet. Med., 2018 Jun). In addition, it was reported in a German individual who met Bethesda criteria and was diagnosed with MSI-H colorectal cancer at age 38 that displayed loss of both MSH2/MSH6 expression by IHC, but no mutations in MSH2 were detected (Steinke V et al. Eur. J. Hum. Genet., 2008 May;16:587-92). Of note, this alteration is also designated as 1013delCTT, c.3037_3039delAAG and p.Lys1013del in published literature. Based on an internal structural assessment, this alteration disrupts the fold of the lever domain (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This amino acid position is highly conserved through mammals, but not in all 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 17, 2023	This variant causes an in-frame deletion of one amino acid in the lever domain in exon 4 of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with or suspected of having Lynch syndrome (PMID: 12658575, 18301448, 32002723; ClinVar SCV000580309.5, SCV000261496.10), as well as pancreatic cancer (PMID: 26483394) and uterine and/or ovarian cancer (PMID: 29875428, 29684080). This variant has been identified in 1/220392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Lynch syndrome 5 Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Counsyl	Sep 29, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 29, 2023	This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Oct 27, 2022

Variant summary: MSH6 c.3040_3042delAAG (p.Lys1014del) results in an in-frame deletion that is predicted to remove one amino acids from DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein. The variant allele was found at a frequency of 4.5e-06 in 220392 control chromosomes (gnomAD). c.3040_3042delAAG has been reported in the literature in comprehensively genotyped individuals affected with Lynch syndrome and associated tumors, supported by characteristic IHC and MSI findings (example, Wagner_2003, Steinke_2008, Hu_2016, Turner_2019, Morak_2020). These data indicate that the variant is 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. Multiple laboratories reported the variant with conflicting assessments (pathogenic (n=1), likely pathogenic, n=2, VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Lynch syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 20, 2023

This variant causes an in-frame deletion of one amino acid in exon 4 of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with, or suspected of having Lynch syndrome (PMID: 12658575, 18301448, 32002723, Keinath 2011), colorectal cancer (http://www.insight-database.org/), uterine and ovarian cancer (PMID: 29875428), uterine cancer (PMID: 29684080), or pancreatic cancer (PMID: 26483394). This variant has been identified in 1/220392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This variant, c.3040_3042del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Lys1014del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs753885956, gnomAD 0.001%). This variant has been observed in individuals with Lynch syndrome (PMID: 12658575, 18301448, 26483394; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 1013delCTT and c.3037_3039delAAG, p.Lys1013del. ClinVar contains an entry for this variant (Variation ID: 89333). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 16, 2024

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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: rs267608073; hg19: chr2-48028158;