2-47803500-AC-ACC
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000179.3(MSH6):c.3261dupC(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
Consequence
NM_000179.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000598 AC: 9AN: 150380Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000562 AC: 82AN: 1459662Hom.: 0 Cov.: 33 AF XY: 0.0000606 AC XY: 44AN XY: 726236
GnomAD4 genome 0.0000598 AC: 9AN: 150380Hom.: 0 Cov.: 32 AF XY: 0.0000682 AC XY: 5AN XY: 73328
ClinVar
Submissions by phenotype
Lynch syndrome 5 Pathogenic:13
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PVS1, PS4_STR, BS1 -
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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. -
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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. -
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. -
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. -
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 -
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. -
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. -
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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not provided Pathogenic:13
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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) -
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PP1, PP4, PP5, PS4_moderate, PVS1 -
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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. This variant has been reported in the published literature in individuals with colorectal cancer (PMID: 34178123 (2021), 32658311 (2021), 28481244 (2017), 24100870 (2013)), ovarian cancer (PMID: 32068069 (2020)), breast cancer (PMID: 32060697 (2020)), and endometrial cancer (PMID: 29442399 (2018), 28523262 (2017), 17453009 (2007), 17117178 (2006)). This variant has also been reported in individuals with prostate cancer (PMID: 25117503 (2014)) and pancreatic cancer (PMID: 29945567 (2018)). The frequency of this variant in the general population, 0.00012 (3/24758 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
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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)). -
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MSH6: PVS1, PP1:Strong, PS4 -
Lynch syndrome Pathogenic:7
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. -
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. -
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PVS1; PP4_MOD -
Coding sequence variation resulting in a stop codon -
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. -
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. -
Hereditary cancer-predisposing syndrome Pathogenic:4
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/). -
The c.3261dupC pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a duplication of C at nucleotide position 3261, causing a translational frameshift with a predicted alternate stop codon (p.F1088Lfs*5). This well-characterized mutation has been reported in multiple individuals and families with Lynch syndrome-associated cancers (Akiyama Y et al. Cancer Res. 1997 Sep;57:3920-3; Shin KH et al. J. Hum. Genet. 1999;44:18-21; Plaschke J et al. J. Clin. Oncol. 2004 Nov;22:4486-94; Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354:2751-63; Kets CM et al. Br. J. Cancer. 2006 Dec;95:1678-82; Overbeek LI et al. Br. J. Cancer. 2007 May;96:1605-12; Talseth-Palmer BA et al. Hered. Cancer Clin. Pract. 2010 May;8:5; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85; Rosty C et al. Fam. Cancer. 2014 Dec;13:573-82; Liccardo R et al. Int. J. Mol. Sci. 2017 May;18:5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
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. -
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Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Pathogenic:2
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PM2_Supporting+PVS1+PM3 -
MSH6-related disorder Pathogenic:2
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. -
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. -
Endometrial carcinoma Pathogenic:2
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Breast and/or ovarian cancer Pathogenic:1
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Inherited MMR deficiency (Lynch syndrome) Pathogenic:1
PVS1,PS4_Very Strong,PP4_Very Strong -
Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Pathogenic:1
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Lynch-like syndrome Pathogenic:1
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Gastric cancer Pathogenic:1
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Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
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). 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 pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. ClinVar contains an entry for this variant (Variation ID: 89364). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at