rs760190301
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000179.3(MSH6):c.3934_3937dupGTTA(p.Ile1313SerfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,462 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
Publications
- intellectual developmental disorder with dysmorphic facies and behavioral abnormalitiesInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461462Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727026 show subpopulations
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in at least two individuals with a clinical history of a Lynch syndrome-associated cancer and/or colon polyps, as well as individuals also diagnosed with breast cancer (Susswein et al., 2015; Yurgelun et al., 2015; Palmer et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 31447099, 30787465, 12019211, 17531815, 21120944, 25980754, 30612635, 32427313, 28369758, 18625694) -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.3934_3937dupGTTA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of GTTA at nucleotide position 3934, which is predicted to cause a translational frameshift with an alternate stop codon (p.I1313Sfs*7). In addition, in silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This alteration occurs at the 3' terminus of the MSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 93 amino acids of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in patients with Lynch syndrome-associated cancers (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20; Susswein LR et al. Genet Med, 2016 08;18:823-32). This mutation has also been observed in the homozygous state in a child with clinical features consistent with constitutional mismatch repair deficiency (CMMRD) (Polubothu S et al. Br. J. Dermatol. 2017 11;177(5):e185-e186). This alteration was also detected in 1/5054 African American women with breast cancer (Palmer JR et al. J Natl Cancer Inst, 2020 12;112:1213-1221). 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. -
This variant inserts 4 nucleotides in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the ATPase and C-terminal MSH2-binding domains (PMID: 12019211, 21120944). This variant has been reported in individuals affected with Lynch/suspected Lynch syndrome (PMID: 18625694, 25980754) , breast, colorectal, endometrial cancer (PMID:26681312), or in a homozygous individual affected with constitutional mismatch repair (PMID: 28369758). This variant has not been identified 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. -
Endometrial carcinoma Pathogenic:2
The MSH6 p.Ile1313SerfsX7 variant was identified in 2 of 23380 proband chromosomes (frequency: 0.00009) from individuals or families undergoing hereditary cancer panel testing or with a history of Lynch syndrome associated cancer and/or polyps (Yurgelun_2015_25980754 , Susswein_2015_26681312). In a case report, a 23-month-old female presenting with abnormal cutaneous pigmentation since birth and a past history of mediastinal non-Hodgkin lymphoma diagnosed at 9 months was found to carry the variant in biallelism, being the offspring of a consanguineous marriage (the grandfathers were brothers) (Polubothu_2017_ 28369758 ). The variant was also identified in ClinVar (classified pathogenic by GeneDx, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (2x), UMD-LSDB (5x as causal), and was not identified in dbSNP, GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3934_3937dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1313 and leads to a premature stop codon 7 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder.rnIn summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
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Lynch syndrome 5 Pathogenic:1
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Lynch syndrome Pathogenic:1
The p.Ile1313SerfsX7 variant in MSH6 has been reported in the heterozygous state in 2 individuals with clinical features of Lynch syndrome and in the homozygous state in one individual with constitutional mismatch repair deficiency syndrome (CMMRD; Yurgelun 2015, Susswein 2015, Polubothu 2017). This variant has also be en reported by other clinical laboratories in ClinVar (Variation ID: 418610) and was absent from large population databases. In vitro functional studies provide some evidence that the p.Ile1313SerfsX7 variant may impact protein function by disrupting the MSH2 interaction domain of MSH6 (Guerrette 1998). However, these types of assays may not accurately represent biological function. This variant i s predicted to cause a frameshift, which alters the protein?s amino acid sequenc e beginning at position 1313 and leads to a premature termination codon 7 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NM D) and result in a truncated protein. Another variant at this position (c.3932_3 935dupAAGT), resulting in the same amino acid change, was classified as pathogen ic on Sept 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000108166.2) . In summary, this variant meets criteria to be classified as pathogenic for Lyn ch Syndrome in an autosomal dominant manner based upon its presence in affected individuals, absence from the general population, functional evidence, having th e same amino acid change as an established pathogenic variant and the predicted impact on the protein. ACMG/AMP Criteria applied: PS1, PVS1_Strong, PM2, PS3_Su pporting, PS4_Supporting. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Ile1313Serfs*7) in the MSH6 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency syndrome, family history of Lynch syndrome-associated cancers, and/or personal history of Lynch syndrome-associated cancers (PMID: 25980754, 26681312, 28369758). 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: 418610). Studies have shown that this premature translational stop signal results in skipping of exon 9 and introduces a new termination codon (internal data). However the mRNA is not expected to undergo nonsense-mediated decay. 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