Submissions for variant NM_000179.3(MSH6):c.3957dup (p.Ala1320fs)

dbSNP: rs587779297

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002524137	SCV003321867	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-02-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Ala1320Glufs*6) have been determined to be pathogenic (PMID: 21155762). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 433931). This premature translational stop signal has been observed in individual(s) with breast cancer, endometrial and ovarian cancer, and/or Lynch syndrome (PMID: 18809606, 19459153, 25186627, 25980754, 26552419, 26681312, 26845104, 27456091). This variant is present in population databases (rs587779297, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ala1320Serfs*5) 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.
Ambry Genetics	RCV003278849	SCV004007744	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-06	criteria provided, single submitter	clinical testing	The c.3957dupA variant, located in coding exon 9 of the MSH6 gene, results from a duplication of A at nucleotide position 3957, causing a translational frameshift with a predicted alternate stop codon (p.A1320Sfs*5). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 41 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003449414	SCV004187132	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	RCV003464073	SCV004196372	likely pathogenic	Endometrial carcinoma	2021-06-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000503361	SCV000592664	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Ala1320SerfsX5 variant was not identified in the literature. It was identified in one database, inSIGHT Colon Cancer database 1X as a pathogenic variant and associated with an MSI-H tumour. It was not identified in any of the following databases: dbSNP, 1000 Genomes Project, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight VariantWire database, and UMD. The p.Ala1320SerfsX5 duplication 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 5 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.