ClinVar Genomic variation as it relates to human health

Coding sequence variation resulting in a stop codon

This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 5 amino acids downstream of the mutation, p.Ala1320Glufs*6. This pathogenic 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. This pathogenic sequence change has been described as an Ashkenazi Jewish founder mutation causing Lynch syndrome (Raskin L, et al., 2011; Laitman Y, et al.,2012). This patient carries this pathogenic sequence change in the MSH6 gene in his germline and has an elevated risk developing MSH6-related Lynch syndrome. Our interpretation is based on the current understanding of MSH6-related Lynch syndrome.

The MSH6 c.3959_3962del (p.Ala1320GlufsTer6) variant results in the deletion of four nucleotides starting at position c.3959 and ending at position c.3962, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. The new stop codon is located near the three prime end of the penultimate exon and therefore nonsense-mediated mRNA decay is not expected to occur. This variant has been reported as an Ashkenazi-Jewish founder variant (PMID: 21155762). Across a selection of the available literature, the c.3959_3962del variant has been reported in at least ten patients with colorectal cancer (PMID: 15872200; PMID: 20028993; PMID: 21155762; PMID: 28944238). This variant has also been reported in patients with cancers of the endometrium (PMID: 12732731; PMID: 15098177; PMID: 26689913), breast (PMID: 30498870), and pancreas (PMID: 29922827). This variant disrupts the very last 40 amino acids of the MSH6 protein, a region that overlaps a binding site for its binding partner MSH2 (PMID: 9774676). This variant is reported in the non-cancer population of the Genome Aggregation Database in two alleles at a frequency of 0.00021 in the Ashkenazi-Jewish population (version 2.1.1). Based on the available evidence, the c.3959_3962del (p.Ala1320GlufsTer6) variant is classified as pathogenic for Lynch syndrome.

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.Ala1320Glufs*6) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the MSH6 protein. This variant is present in population databases (rs267608119, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with clinical features of MSH6-related conditions (PMID: 12732731, 20007843, 20028993, 21155762, 23990280, 24440087, 25430799, 26544533). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 21155762). This variant is also known as 3956_3959delAAGC. ClinVar contains an entry for this variant (Variation ID: 89488). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 19851887, 21155762, 24440087). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This variant deletes 4 nucleotides in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal in the last coding exon. 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 impact the ATPase domain and the MSH2 binding domain. This variant has been reported in individuals affected with Lynch syndrome or colorectal/endometrial cancers along with clinical features of Lynch syndrome (PMID: 20028993, 21155762, 22219001, 23990280, 25430799), constitutional mismatch repair syndrome (PMID: 24440087, 26544533), or breast cancer (PMID: 30498870). This variant has been identified in 4/248908 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.

The p.Ala1320GlufsX6 variant in MSH6 has been reported in >15 individuals with Lynch Syndrome-associated cancers (Goodfellow 2003 PMID: 12732731, Hampel 2005 PMID: 15872200, Raskin 2011 PMID: 21155762, Goldberg 2014 PMID: 23990280, Yurgelun 2015 PMID: 25980754, Lu 2015 PMID: 26689913, DeRycke 2017 PMID: 28944238, Bernstein-Molho 2019 PMID: 30980208) and is believed to be an Ashkenazi Jewish founder variant (Raskin 2011 PMID: 21155762). It has also been reported in the compound heterozygous state in two families with constitutional mismatch repair deficiency CMMRD) syndrome (CMMRD), where the variant was identified in trans with a second pathogenic variant in MSH6 (Bakry 2014 PMID: 24440087, Shapira Rootman 2020 PMID: 31730237). Additionally, this variant segregated with CMMRD in 2 affected siblings (Bakry 2014 PMID: 24440087). This variant has been identified in 0.03% (3/10024) of Ashkenazi Jewish chromosomes and in 0.009% (1/112292) 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 1320 and leads to a premature termination codon 6 amino acids downstream. This termination codon occurs within the terminal 50 bases of the penultimate exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing less than 3% of the coding region, with 34 amino acids removed. Tumors from two patients with this variant have been found to have loss of MSH6 protein expression (Raskin 2011 PMID: 21155762, Bakry 2014 PMID: 24440087). Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with autosomal dominant Lynch syndrome. Additionally, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89488). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch Syndrome (ACMG/AMP Criteria applied: PS4, PS3_Moderate, PVS1_Moderate, PM2_Supporting) and autosomal recessive CMMRD (ACMG/AMP Criteria applied: (PM3_Strong, PVS1_Moderate, PS3_Moderate, PP1_Moderate, PM2_Supporting).

The c.3959_3962delCAAG pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a deletion of 4 nucleotides at nucleotide positions 3959 to 3962, causing a translational frameshift with a predicted alternate stop codon (p.A1320Efs*6). This mutation has been reported as an Ashkenazi Jewish founder mutation for Lynch syndrome (Raskin L et al. Clin. Genet. 2011 Jun:79:512-22; Goldberg Y et al. Fam. Cancer. 2014 Mar;13:65-73). It has been identified in numerous individuals with Lynch syndrome tumors, including several with tumors demonstrating microsatellite instability and/or absent MSH6 on IHC (Goodfellow PJ et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100:5908-13; Hampel H et al. N. Engl. J. Med. 2005 May;352:1851-60; Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201). In addition, the international consortium of childhood constitutional mismatch repair deficiency (CMMRD) reported this deletion in three individuals with CMMRD: one with GI polyposis, one with T-cell lymphoma and GI polyposis, and one with glioblastoma multiforme (Bakry D et al. Eur. J. Cancer. 2014 Mar;50:987-96). 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.

MSH6: PVS1:Strong, PM2, PP1:Moderate, PS4:Moderate

Variant summary: The MSH6 c.3959_3962delCAAG (p.Ala1320Glufs) variant 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. If this variant escapes NMD, it is expected to truncate P-loop containing nucleoside triphosphate hydrolase. Other similar truncations variants in this gene have been classified as pathogenic by our laboratory (e.g. p.Ala1320fs). This variant is absent in 122768 control chromosomes. This variant has been reported in literature as a pathogenic variant found in several patients with Lynch syndrome related cancers (Goodfellow_2003, Raskin_2015). It is regarded as a founder mutation in Ashkenazi Jews. Multiple clinical labs/reputable databases have classified it as pathogenic. Taken together, this variant is classified as Pathogenic.

The c.3959_3962delCAAG (p.Ala1320Glufs*6) frameshift variant in the MSH6 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with Lynch Syndrome associated tumors (PMID: 15872200, 20007843, 20028993, 21155762, 23990280, 24440087). This variant is also extremely rare in the population according to gnomAD (4/243772). Therefore, the c.3959_3962delCAAG (p.Ala1320Glufs*6) variant in the MSH6 gene is classified as pathogenic.

Common founder variant in the Ashkenazi Jewish population (Cox 2018); Frameshift variant predicted to result in protein truncation 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 individuals with MSH6-related cancers (Goodfellow 2003, Raskin 2011, Goldberg 2014, DeRycke 2017); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.3956_3959delAAGC; This variant is associated with the following publications: (PMID: 12732731, 21155762, 20028993, 23206658, 25430799, 28873162, 30152102, 29946849, 26544533, 29922827, 24440087, 22219001, 26822575, 25642631, 24371622, 26823682, 25345868, 23990280, 20007843, 29485237, 30498870, 31730237, 28944238, 29625052, 32719484, 30787465, 26689913, 31447099)

This frameshift variant causes the premature termination of MSH6 protein synthesis. In addition, it has been reported in individuals with Lynch Syndrome and Constitutional Mismatch Repair Deficiency (CMMRD) syndrome in the published literature and is a founder mutation in the Ashkenazi Jewish population (PMIDs: 30498870 (2019), 26544533 (2016), 25430799 (2015), 24440087 (2014), 21155762 (2011), 20028993 (2010), and 12732731 (2003)). Based on the available information, this variant is classified as pathogenic

This variant deletes 4 nucleotides in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal in the last coding exon. 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 impact the ATPase domain and the MSH2 binding domain. This variant has been reported in individuals affected with Lynch syndrome or colorectal/endometrial cancers along with clinical features of Lynch syndrome (PMID: 20028993, 21155762, 22219001, 23990280, 25430799), constitutional mismatch repair syndrome (PMID: 24440087, 26544533), or breast cancer (PMID: 30498870). This variant has been identified in 4/248908 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.

PVS1_Moderate,PS4_Very Strong,PM3_Supporting,PP4

The p.3959_3962delCAAG deletion variant was identified in 7 of 6956 proband chromosomes (frequency: 0.001) from Israeli individuals with familial and sporadic gastric and pancreatic cancers, and both Ashkenazi Jewish(AJ) and non-AJ individuals or families with endometrial and colorectal cancers, unselected for family history and age at diagnosis; and was not identified in 3310 control chromosomes from healthy individuals (Goodfellow 2003, Hampel 2005, Hampel 2005, Raskin 2010, Laitman 2012). The variant was also found in 3/32 patients from 14 kindreds with CMMRD (Constitutional Mismatch Repair Deficiency), a cancer predisposition syndrome in children characterized by homozygous/biallelic MMR gene mutations and the development of hematological, brain and gastrointestinal cancers; co-occurring with c.3984_3987dup mutation (Bakry 2014). Raskin (2010) identified the c.3959_3962delCAAG variant as a founder mutation causing Lynch syndrome in the AJ population. A study looking at penetrance and expressivity of pathogenic germline MSH6 mutations which included this variant, showed that patients carrying these mutations were at increased risk of cancer (specific tumour spectrum undefined), with 58% penetrance, and later onset than that seen in MSH2 or MLH1 mutant carriers (Buttin 2004). The variant was also identified in HGMD, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database, the ClinVar database (classified as a pathogenic variant by Insight, and reviewed by an expert panel as pathogenic), and UMD (10X as a causal variant). The p.Ala1320GlufsX6 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1320 and leads to a premature stop codon 6 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. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

Variant interpreted as Pathogenic and reported on 12-08-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.