Submissions for variant NM_000179.3(MSH6):c.3966dup (p.Phe1323fs)

dbSNP: rs886044911

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539680	SCV000624951	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-04-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe1323Ilefs*2) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 38 amino acid(s) of the MSH6 protein. 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: 291306). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 14520694, 19851887, 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.
Ambry Genetics	RCV002356397	SCV002623051	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-11	criteria provided, single submitter	clinical testing	The c.3966dupA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of A at nucleotide position 3966, causing a translational frameshift with a predicted alternate stop codon (p.F1323Ifs*2). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 38 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). Another truncating alteration downstream, p.C1337Sfs*5 (c.4004_4007dupAAGT), has been observed in at least one individual with a personal and/or family history that is consistent with Lynch syndrome (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003454836	SCV004185806	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	RCV004567839	SCV005054892	likely pathogenic	Endometrial carcinoma	2024-02-26	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Wuerzburg	RCV000351125	SCV000346027	pathogenic	Hereditary nonpolyposis colorectal carcinoma		no assertion criteria provided	clinical testing