rs63749942

chr2-47806278-TGTC-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000179.3(MSH6):c.3724_3726del(p.Arg1242del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. C1241C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MSH6 NM_000179.3 inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 7.66

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 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in NM_000179.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000179.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-47806278-TGTC-T is Pathogenic according to our data. Variant chr2-47806278-TGTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 89450.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47806278-TGTC-T is described in Lovd as [Likely_pathogenic]. Variant chr2-47806278-TGTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3724_3726del	p.Arg1242del	inframe_deletion	8/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3724_3726del	p.Arg1242del	inframe_deletion	8/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251212 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135748

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461778 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 5 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 25, 2023	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20028993, 17718861]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 15, 2021	ACMG classification criteria: PM2 moderate, PM4 moderate, PP1 supporting -

Lynch syndrome Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 21, 2019	Multifactorial likelihood analysis posterior probability 0.95-0.99 -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 08, 2023	This variant causes a deletion of the conserved arginine at codon 1242 located in the ATPase domain 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 Lynch syndrome (PMID: 20028993; ClinVar SCV000183865.7), colorectal cancer (PMID: 17718861), and endometrial cancer (PMID: 24933100, 27443514). This variant has been shown to segregate with colorectal cancer in three members of a family (PMID: 17718861). Loss of MSH6 protein expression has been observed in tumor tissues from two affected carriers (PMID: 17718861, 24933100). This variant has also been observed in an individual affected with constitutional mismatch repair deficiency who carried a pathogenic MSH6 variant in trans (ClinVar SCV000183865.7). A multifactorial likelihood analysis using genetic data, computational prediction and tumor pathology has indicated that this variant has a high probability of being pathogenic (PMID: 24362816). This variant has been identified in 2/251212 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Missense variants occurring at this codon, p.Arg1242His and p.Arg1242Ser, are thought to be disease-causing (Clinvar variation ID: 140866, 89449), indicating the importance of arginine at this codon for MSH6 protein function. Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 09, 2022	The frequency of this variant in the general population, 0.000008 (2/251212 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMIDs: 28514183 (2017), 27443514 (2016), and 20028993 (2010)), colorectal cancer (PMIDs: 33654310 (2021) and 17718861 (2007)), and endometrial cancer (PMID: 24933100 (2014)). The variant was found to co-segregate with disease within a family with rectum cancer, colon cancer, endometrial cancer, or polyps (PMID: 17718861 (2007)). Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2020	In-frame deletion of 1 amino acid in a non-repeat region; Observed in individuals with endometrial, skin, and colorectal cancer, segregating with disease in at least one family, and immunohistochemistry (IHC) of one rectal and one endometrial tumor revealed absence of MSH6 protein (Roncari 2007, Batte 2014, Ring 2016, Ponz de Leon 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 17718861, 24933100, 24763289, 20028993, 24362816, 27443514, 29025352) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 10, 2023	This variant causes a deletion of the conserved arginine at codon 1242 located in the ATPase domain 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 Lynch syndrome (PMID: 20028993; ClinVar SCV000183865.7), colorectal cancer (PMID: 17718861), and endometrial cancer (PMID: 24933100, 27443514). This variant has been shown to segregate with colorectal cancer in three members of a family (PMID: 17718861). Loss of MSH6 protein expression has been observed in tumor tissues from two affected carriers (PMID: 17718861, 24933100). This variant has also been observed in an individual affected with constitutional mismatch repair deficiency who carried a pathogenic MSH6 variant in trans (ClinVar SCV000183865.7). A multifactorial likelihood analysis using genetic data, computational prediction and tumor pathology has indicated that this variant has a high probability of being pathogenic (PMID: 24362816). This variant has been identified in 2/251212 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Missense variants occurring at this codon, p.Arg1242His and p.Arg1242Ser, are thought to be disease-causing (Clinvar variation ID: 140866, 89449), indicating the importance of arginine at this codon for MSH6 protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 15, 2021	The c.3724_3726delCGT pathogenic mutation (also known as p.R1242del) is located in coding exon 8 of the MSH6 gene. This variant results from an in-frame CGT deletion at nucleotide positions 3724 to 3726. This results in the in-frame deletion of an arginine at codon 1242. This alteration was identified in an individual diagnosed with an MSH6-deficient rectal cancer at age 42 and a family history meeting the Amsterdam II criteria; this same alteration was present in this individual's brother, who was diagnosed with rectal cancer at age 53, and mother, who was diagnosed with endometrial cancer at age 54 and ascending colon cancer at age 78 (Roncari B et al. Clin. Genet. 2007 Sep;72:230-7). This alteration has also been reported in multiple other patients with a personal and/or family history consistent with Lynch syndrome, including several demonstrating loss of MSH6 protein by immunohistochemistry (IHC) analysis (Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201; Batte BA et al. Gynecol. Oncol. 2014 Aug;134(2):319-25; Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-1389; Ambry internal data). In addition, a missense variant impacting codon 1242 (p.R1242H) has been detected in trans with a pathogenic MSH6 mutation in an individual whose clinical presentation was consistent with CMMR-D due to biallelic MSH6 mutations and had isolated absence of MSH6 in both tumor and normal tissue by IHC (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Nov 22, 2022

Variant summary: MSH6 c.3724_3726delCGT (p.Arg1242del) results in an in-frame deletion that is predicted to remove one amino acids from the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of encoded protein. The variant allele was found at a frequency of 8e-06 in 251212 control chromosomes (gnomAD). c.3724_3726delCGT has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and endometrial cancer (e.g. Roncari_2007, Batte_2014, Espenschied_2017, Bennett_2021) and was shown to co-segregate with disease in at least one HNPCC family (Roncari_2007). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters including one expert panel (InSiGHT) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Lynch-like syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Constitutional Genetics Lab, Leon Berard Cancer Center

Jul 01, 2019

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This variant, c.3724_3726del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Arg1242del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587781362, gnomAD 0.002%). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 17718861, 20028993, 22144684, 24933100, 27443514). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89450). This variant disrupts the p.Arg1242 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23729658, 24763289). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 24, 2022

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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: rs63749942; hg19: chr2-48033417;