ClinVar Genomic variation as it relates to human health

Variant summary: MSH6 c.3980_3983dupATCA (p.Leu1330ValfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 246946 control chromosomes. c.3980_3983dupATCA has been reported in the literature in multiple individuals affected with Lynch syndrome and features of CMMRD (constitutional mismatch repair deficiency) (example, Baglietto_2010, Gardes_2012, Epsenschied_2017, Toledano_2019, Rootman_2020, Dong_2020). These data indicate that the variant is very 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. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Observed as homozygous in a patient with constitutional mismatch repair deficiency (CMMR-D) (Toledano et al., 2019); Observed as heterozygous in individuals with a personal or family history consistent with pathogenic variants in this gene (Baglietto et al., 2010; Yang et al., 2021); Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 31730237, 28152038, 31447099, 34148862, 36988593, 32844218, 34086170, 20028993, 29922827, 32030746, 31501241, 33977078)

The p.Leu1330fs (c.3984_3987dupATCA) variant in MSH6 has been reported in at least 1 individual with Lynch syndrome-associated cancers (Baglietto 2010 PMID: 20028993) and in homozygous state in 1 individual with constitutional mismatch repair deficiency syndrome (CMMRD; Shapira Rootman 2020 PMID: 31730237, Toledano 2020 PMID: 31501241). Additionally, another variant at this position (c.3984_3987dupGTCA) leading to the same frameshift has been described as an Ashkenazi Jewish founder variant and has been shown to cause loss of expression of MSH6 protein (Goldberg 2010 PMID: 19851887). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 184998) and has been identified in 1/111536 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1330 and leads to a premature termination codon 12 amino acids downstream. Although this termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD), the available evidence from the other Ashkenazi Jewish founder variant shows that the variant ultimately leads to loss of function. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon the predicted impact to the protein and the presence of an established pathogenic variant with the same amino acid change. ACMG/AMP Criteria applied: PS1; PVS1_Strong, PM2_Supporting.

The c.3980_3983dupATCA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of ATCA at position 3980 to 3983, causing a translational frameshift with a predicted alternate stop codon (p.L1330Vfs*12). This alteration was identified once from a pool of Scottish probands with either colon or endometrial cancer diagnosed before age 55 (Baglietto L et al. J Natl Cancer Inst. 2010 Feb 3;102(3):193-201) and was reported homozygous in an individual with CMMRD (Shapira Rootman M et al. Clin Genet, 2020 02;97:296-304). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, 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 expected to result in an absent or non-functional protein product. This variant has been identified in 1/246946 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.

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

This sequence change creates a premature translational stop signal (p.Leu1330Valfs*12) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the MSH6 protein. This variant is present in population databases (rs786204180, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of MSH6-related conditions (PMID: 14520694, 19851887, 20028993, 24440087). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 184998). For these reasons, this variant has been classified as Pathogenic.

The MSH6 p.Leu1330ValfsX12 variant was identified in 3 of 69962 proband chromosomes (frequency: 0.00004) from individuals or families with lynch syndrome (Espenschied 2017). The variant was also identified in dbSNP (ID: rs786204180) as N/A, ClinVar (classified as pathogenic by Ambry Genetics, Invitae, GenDxl; classified as likely pathogenic by Mayo Clinic), Clinvitae (classified as pathogenic by ClinVar and Invitae), databases. The variant was not identified in UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.3980_3983dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1330 and leads to a premature stop codon at position 1341. 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. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.