Submissions for variant NM_000179.3(MSH6):c.2290dup (p.Thr764fs)

dbSNP: rs1553413663

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575646	SCV000662576	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-27	criteria provided, single submitter	clinical testing	The c.2290dupA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of A at nucleotide position 2290, causing a translational frameshift with a predicted alternate stop codon (p.T764Nfs*8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000657404	SCV000779138	pathogenic	not provided	2017-11-03	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in MSH6 is denoted c.2290dupA at the cDNA level and p.Thr764AsnfsX8 (T764NfsX8) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TGAT[dupA]CTTG. The duplication causes a frameshift which changes a Threonine to an Asparagine at codon 764, and creates a premature stop codon at position 8 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000575646	SCV001354406	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-21	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 4 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. To our knowledge, this variant has not been reported in individuals affected with MSH6-related disorders in the literature. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858113	SCV002246074	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-06-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr764Asnfs*8) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 479967). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003451221	SCV004185738	pathogenic	Lynch syndrome 5	2023-08-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767392	SCV005380786	pathogenic	Hereditary nonpolyposis colon cancer	2024-08-09	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2290dupA (p.Thr764AsnfsX8) 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. The variant was absent in 251148 control chromosomes. c.2290dupA has been reported in the literature in at-least one individual affected with Lynch Syndrome (example: Yang_2021). The following publication has been ascertained in the context of this evaluation (PMID: 34178123). ClinVar contains an entry for this variant (Variation ID: 479967). Based on the evidence outlined above, the variant was classified as pathogenic.