Submissions for variant NM_000179.3(MSH6):c.3980_3983dup (p.Leu1330fs)

dbSNP: rs1553333738

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164350	SCV000214983	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-08	criteria provided, single submitter	clinical testing	The c.3980_3983dupATCA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of ATCA at nucleotide positions 3980 to 3983, causing a translational frameshift with a predicted alternate stop codon (p.L1330Vfs*12). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 2.3% of the protein. However, premature stop codons are typically deleterious in nature. This mutation was identified once in 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 in individuals meeting Amsterdam criteria (Ambry internal data). In addition, this mutation was reported as homozygous in an individual with constitutional mismatch repair deficiency (CMMRD) (Shapira Rootman M et al. Clin Genet, 2020 02;97:296-304). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168228	SCV000218896	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-12	criteria provided, single submitter	clinical testing	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. 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: 184998). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000202005	SCV000568734	pathogenic	not provided	2023-07-25	criteria provided, single submitter	clinical testing	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)
Color Diagnostics, LLC DBA Color Health	RCV000164350	SCV000905461	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826202	SCV000967756	pathogenic	Lynch syndrome	2021-10-27	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000202005	SCV001250455	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420827	SCV001623216	pathogenic	Hereditary nonpolyposis colon cancer	2021-05-01	criteria provided, single submitter	clinical testing	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.
MGZ Medical Genetics Center	RCV002288734	SCV002579310	likely pathogenic	Lynch syndrome 5	2021-07-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288734	SCV004188235	pathogenic	Lynch syndrome 5	2023-08-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003462132	SCV004198146	pathogenic	Endometrial carcinoma	2022-06-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202005	SCV005623504	pathogenic	not provided	2024-11-06	criteria provided, single submitter	clinical testing	The MSH6 c.3980_3983dup (p.Leu1330Valfs*12) 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 affected with colon cancer and endometrial cancer (PMIDs: 38722212 (2024), 32844218 (2021)) as well as constitutional mismatch repair deficiency (CMMRD) syndrome (PMIDs: 31730237 (2020), 31501241 (2020)). Other published studies have shown that this variant has deleterious effects on the expression and function of the MSH6 protein (PMIDs: 22250089 (2012), 32844218 (2021)). The frequency of this variant in the general population, 0.000004 (1/246946 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202005	SCV000257290	likely pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358035	SCV001553672	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	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.
Laboratory for Genotyping Development, RIKEN	RCV003162687	SCV002758273	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research