2-47803500-A-AC

Position:

• chr2-47803500-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000179.3(MSH6):​c.3261dup​(p.Phe1088LeufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000565 in 1,610,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:45
• Conservation: PhyloP100: 0.649

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-47803500-A-AC is Pathogenic according to our data. Variant chr2-47803500-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 89364.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3261dup	p.Phe1088LeufsTer5	frameshift_variant	5/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3261dup	p.Phe1088LeufsTer5	frameshift_variant	5/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes AF: 0.0000598 AC: 9 AN: 150380 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000490

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: 0.0000964

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000888

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000562 AC: 82 AN: 1459662 Hom.: 0 Cov.: 33 AF XY: 0.0000606 AC XY: 44 AN XY: 726236

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000303

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000598 AC: 9 AN: 150380 Hom.: 0 Cov.: 32 AF XY: 0.0000682 AC XY: 5 AN XY: 73328

Gnomad4 AFR AF: 0.0000490

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000964

Gnomad4 NFE AF: 0.0000888

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:45

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2020	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Hampel 2008, Sjursen 2010, Terui 2013, Kumamoto 2015, Rubio 2016, Lee 2017, Suzuki 2017, Tian 2019) Observed in the homozygous and compound heterozygous state in patients with constitutional mismatch repair deficiency in published literature (Ilencikova 2011, Ling 2018) Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database Not observed at a significant frequency in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 32068069, 32029870, 32658311, 32832836, 31447099, 32060697, 18809606, 20587412, 24100870, 26249337, 27398995, 28523262, 28258479, 31054147, 30147880, 21674763, 29945567, 31297992, 19526325, 30322717, 23757202, 28481244, 28514183, 28332257, 28502729, 26681312, 24068316, 26318770, 27978560, 27446556, 25980754, 24689082, 9307272, 25117503, 28724667, 28944238, 28491141, 28195393, 20028993, 20045164, 25194673, 25110875, 26845104, 17117178, 12658575, 15837969, 18301448, 9929971, 15365995, 15483016, 16807412, 17453009, 20487569) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MSH6: PVS1, PP1:Strong, PS4 -
Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 02, 2022	DNA sequence analysis of the MSH6 gene demonstrated a 1 base pair duplication in exon 5, c.3261dup. This sequence change results in an amino acid frameshift and creates a premature stop codon 5 amino acids downstream of the change, p.Phe1088Leufs*5. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated MSH6 protein with potentially abnormal function. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in the gnomAD population database at a frequency of 0.012% in the African subpopulation (dbSNP rs1361078163), however this data is not considered reliable, as metrics indicate poor data quality at this position in the gnomAD database. This pathogenic sequence change has previously been described in individuals with Lynch syndrome (PMID: 9929971, 15483016, 26318770)). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 12, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 07, 2023	PP1, PP4, PP5, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 04, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 10, 2020	The MSH6 c.3261dup (p.Phe1088Leufs*5) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. The frequency of this variant in the general population, 0.00012 (3/24758 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals and families with Lynch syndrome-related cancers (PMIDs: 18301448 (2008), 20487569 (2010), 24100870 (2013), 24689082 (2014), 25980754 (2015), 28481244 (2017)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 24, 2014	- -

Lynch syndrome 5 Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Mar 04, 2019	The c.3261dupC variant is a known pathogenic variant in the MSH6 gene. This variant results in the substitution of a leucine for a phenylalanine at codon 1088 and a premature stop codon five residues downstream. The MSH6 c.3261dupC variant has been reported in a number of individuals with Lynch syndrome-associated cancers (Sjursen 2010, Terui 2013, McCarthy 2018). In addition, this variant has been reported in the homozygous state in three children from a consanguineous family that all had constitutional mismatch repair deficiency (Ilencikova 2011). Therefore, we interpret c.3261dupC as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Oct 15, 2024	This variant has been identified by standard clinical testing. female patient with bilateral breast cancer, endometrial cancer and ovarian cancer Selected ACMG criteria: Pathogenic (I):PP5;PS4;PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Aug 10, 2022	The c.3261dup;p.(Phe1088Leufs*5) is a null frameshift variant (NMD) in the MSH6 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 89364; PMID: 28466842; 28523262; 28502729; 32660107; 30387329; 32449172) -PS4. The variant is present at low allele frequencies population databases (rs267608078 – gnomAD 0.0005985%; ABraOM no frequency - https://abraom.ib.usp.br/) -PM2_supporting.The p.(Phe1088Leufs*5) was detected in trans with a pathogenic variant (PMID: 26318770) - PM3_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 29, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS4_STR, BS1 -
Pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_000179.3:c.3261dup (chr2:47803500) in MSH6 was detected in 5 heterozygotes out of 58K WGS Icelanders (MAF= 0,004%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PP5_Strong) this variant classifies as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 31, 2017	This c.3261dupC variant has been reported in multiple individuals with Lynch Syndrome (PMID9929971, 15483016, 26318770), 3 additional patients with colon cancer (PMID17117178, 16807412, 24100870) and 5 more patients with endometrial cancer including 3 from the same family showing co-segregation from one generation to the next (PMID1711717, PMID17453009, PMID15837969). This variant is predicted to cause a frameshift and, and create a premature stop codon. Based upon the above evidence, this c.3261_3262insC variant in the MSH6 gene is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Nov 13, 2023	The MSH6 c.3261dup (p.Phe1088Leufs*5) change duplicates one nucleotide to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in the heterozygous state in individuals with Lynch syndrome as well as in the homozygous and compound heterozygous state in individuals with constitutional mismatch repair deficiency (PMID: 15837969, 24100870, 28491141, 29442399, 30147880, 33924881, 34738371, internal data). In summary, this variant meets criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 29, 2020	The MSH6 gene encodes a component of the DNA mismatch repair (MMR) system. The c.3261dupC variant in MSH6 has been reported in multiple individuals with Lynch Syndrome, an inherited condition that increases the risk of colorectal, endometrial and other cancers. It results in a premature stop codon in exon 5 likely leading to nonsense-mediated decay and lack of protein production. This variant is rare in a large population database (17/280876 total alleles, 0.0061%, no homozygotes) and has been reported in ClinVar. We consider this variant to be pathogenic. -

Lynch syndrome Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 01, 2016	Variant summary: The MSH6 c.3261dupC (p.Phe1088Leufs) variant is located in exon 5 and results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 211/120336 (1/570), which is approximately 12 times the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7031. The high prevalence of the variant in controls can be explained by possibility of sequencing error, although the low penetrance is possibility too. The reason for low penetrance could be the existence of alternative splice acceptor site 7bp downstream of duplicated base, which can result in alternative protein lacking 32 amino acids. The variant of interest has been reported in multiple affected individuals with varying phenotypes, Lynch syndrome, atypical HNPCC, HNPCC (fulfilling either Bethesda or Amsterdam criteria), along with a family that had three homozygous children diagnosed with constitutional mismatch repair deficiency syndrome. In addition, one family (Palmer_2010) did indicate a lack of co-segregation with disease, along with another study, Yurgelun_2015 indicating the variant to have co-occurred with another pathogenic STK11 variant, c.375-1C>T. While other publications did indicate the variant segregated with disease (Akiyama_1997 and Ollikinen_2005). Furthermore, multiple reputable databases/clinical laboratories and publications cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Likely Pathogenic. -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH6 p.Phe1088LeufsX5 duplication variant was identified in 6 of 4432 proband chromosomes (frequency: 0.001) from individuals with suspected Lynch syndrome (phenotype of colorectal or endometrial cancer) (Kets 2006, Ollikainen 2005, Plaschke 2004). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1088 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function of the MSH6 gene is an established disease mechanism in Lynch Syndrome. The p.Phe1088LeufsX5 variant was shown to co-segregate with late-onset endometrial cancer in one family, with 6 members affected across 3 generations (Ollikainen 2005). In addition, the tumours from three individuals in this family, and the tumours from three other individuals positive for this variant (Kets 2006, Plaschke 2004) were deficient for MSH6 protein by IHC. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	The c.3261dup (p.Phe1088Leufs*5) variant in the MSH6 gene is located on the exon 5 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Phe1088Leufs*5), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancers (PMID: 32660107, 34848827, 36387226, 30387329, 30147880, 32664968, 31845022, 31857677). The variant has been also reported in individuals with constitutional mismatch repair-deficiency syndrome in homozygous or compound heterozygous states (PMIS: 21674763, 24068316). Loss-of-function variants in MSH6 are known to be pathogenic and frameshift/truncating variants located downstream to this position have been reported in individuals with Lynch syndrome-associated cancers (PMID: 20028993, 18269114). This variant is reported in ClinVar as pathogenic (ID: 89364) and reviewed by expert panel. The variant is rare in general population according to gnomAD (17/280876). Therefore, the c.3261dup (p.Phe1088Leufs*5) variant of MSH6 has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 20, 2022	The p.Phe1088LeufsX5 variant in MSH6 has been reported in > 20 individuals with MSH6-associated cancers and segregated with disease in >3 affected relatives from 2 families (Akiyama 1997 PMID: 9307272, Plaschke 2004 PMID: 15483016, Ollikainen 2005 PMID: 15837969, Barnetson 2006 PMID: 16807412, Kets 2006 PMID: 17117178, Overbeek 2007 PMID: 17453009, Steinke 2008 PMID: 18301448, Sjursen 2010 PMID: 20587412, Bonadona 2011 PMID: 21642682, Terui 2013 PMID: 24100870, Hansen 2014 PMID: 24689082, Rosty 2014 PMID: 25117503, Susswein 2015 PMID: 26681312). Tumors sampled from some of these individuals lacked MSH6 expression (Ollikainen 2005 PMID: 15837969, Sjursen 2010 PMID: 20587412, Terui 2013 PMID: 24100870, Rosty 2014 PMID: 25117503). Additionally, this variant has been reported in the compound heterozygous state in 1 individual with constitutional mismatch repair deficiency (CMMRD) and family history of MSH6-associated cancers (Bougeard 2014 PMID: 24068316, Lavoine 2015 PMID: 26318770). This variant has also been identified in 0.009% (6/67594) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of MSH6-associated cancers in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1088 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in Lynch syndrome. In addition, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108042.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_Supporting, PS4, PVS1, PS3. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 20, 2022	This variant inserts 1 nucleotide in exon 5 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in individuals and families affected with Lynch syndrome-associated cancer (PMID: 9307272, 9929971, 12658575, 15837969, 16807412, 17117178, 18301448, 24068316, 24100870, 25117503, 25110875, 25980754, 26681312, 28481244), as well as prostate or breast cancer (PMID: 25117503, 26681312). This variant also has been detected in homozygous and compound heterozygous carriers affected with constitutional mismatch repair deficiency syndrome (PMID: 21674763, 24068316, 30147880). This variant has been identified in 17/280876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variation is an insertion of 1 nucleotide in exon 5 of the MSH6 mRNA (c.3261dupC), causing a frameshift at codon 1088. This creates a premature translation stop signal 5 amino acid residues later- p.(Phe1088Leufs*5) and is expected to result in an absent or disrupted protein product. Truncating variants in MSH6 are known to be pathogenic. This mutation has been reported in the literature in individuals with Lynch syndrome, colorectal, endometrial and prostate cancer (PMID: 9307272, PMID: 15483016, PMID: 26318770, PMID: 16807412, PMID: 24100870, (PMID: 25117503 PMID: 15837969). The mutation database ClinVar contains entries for this variant (Variation ID: 89364/). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 31, 2024	The c.3261dupC (p.F1088Lfs*5) alteration, located in coding exon 5 of the MSH6 gene, consists of a duplication of C at position 3261, causing a translational frameshift with a predicted alternate stop codon after amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the CC allele has an overall frequency of 0.006% (17/280876) total alleles studied. The highest observed frequency was 0.028% (2/7178) of Other alleles. This well-characterized mutation has been reported in multiple individuals and families with Lynch syndrome-associated cancers (Akiyama, 1997; Shin, 1999; Plaschke, 2004; Barnetson, 2006; Kets, 2006; Overbeek, 2007; Talseth-Palmer, 2010; Sjursen, 2010; Rosty, 2014). Based on the available evidence, this alteration is classified as pathogenic. -

MSH6-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This frameshifting variant in exon 5 of 10 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in MSH6 is an established mechanism of disease (PMID: 20301390, 18269114). This variant has been previously reported as a homozygous and compound heterozygous change in patients with constitutional mismatch repair deficiency syndrome and as a heterozygous change in patients with Lynch syndrome-associated cancers (PMID: 30147880, 26318770, 21674763, 28481244, 28523262). The c.3261dup (p.Phe1088LeufsTer5) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (17/280876) and thus is presumed to be rare. However, quality metrics indicate the frequency data for this variant in the population databases is considered unreliable in the gnomAD database. Based on the available evidence, c.3261dup (p.Phe1088LeufsTer5) is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 13, 2024	The MSH6 c.3261dupC variant is predicted to result in a frameshift and premature protein termination (p.Phe1088Leufs*5). This variant (also described as 1087insC, c.3524dupC, and c.3261_3262insC) has been reported in multiple individuals with Lynch syndrome and Lynch-associated cancers (Akiyama et al. 1997. PubMed ID: 9307272; Table S1, Baglietto et al. 2010. PubMed ID: 20028993; eTable1, Bonadona et al. 2011. PubMed ID: 21642682; Table S1, DeRycke et al. 2017. PubMed ID: 28944238; Table S1, Carter et al. 2018. PubMed ID: 30322717; Table S3, Yang et al. 2021. PubMed ID: 34178123; Table S1, Gordhandas et al. 2023. PubMed ID: 36744932). It has also been observed in the compound heterozygous state in individuals with constitutional mismatch repair deficiency syndrome (CMMRD) (Lavoine et al. 2015. PubMed ID: 26318770; Ling et al. 2018. PubMed ID: 30147880). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and has been interpreted as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89364/). Frameshift variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Endometrial carcinoma Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Feb 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 19, 2022

- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 27, 2022

- -

Inherited MMR deficiency (Lynch syndrome) Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Apr 17, 2024

PVS1,PS4_Very Strong,PP4_Very Strong -

Lynch-like syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Constitutional Genetics Lab, Leon Berard Cancer Center

Jul 01, 2019

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change creates a premature translational stop signal (p.Phe1088Leufs*5) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 9307272, 9929971, 12658575, 15483016, 15837969, 16807412, 17117178, 17453009, 18301448, 24100870, 24689082, 25117503, 26318770). ClinVar contains an entry for this variant (Variation ID: 89364). For these reasons, this variant has been classified as Pathogenic. -

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: rs267608078; hg19: chr2-48030639;