Submissions for variant NM_000179.3(MSH6):c.1168del (p.Asp390fs)

gnomAD frequency: 0.00002  dbSNP: rs753796271

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491747	SCV000580321	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	The c.1168delG pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 1168, causing a translational frameshift with a predicted alternate stop codon (p.D390Ifs*21). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805110	SCV002051077	pathogenic	Hereditary nonpolyposis colon cancer	2023-11-10	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1168delG (p.Asp390IlefsX21) 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 allele was found at a frequency of 2e-05 in 251000 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1168delG has been reported in the literature in individuals with a personal or family history of Lynch Syndrome-related cancers (e.g., Wu_2015, Feliubadalo_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30927264, 25954033). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV002248719	SCV002517639	pathogenic	Endometrial carcinoma	2022-05-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003449326	SCV004187081	pathogenic	Lynch syndrome 5	2023-08-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003758797	SCV004519703	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp390Ilefs*21) 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 present in population databases (rs753796271, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with undergoing testing for Lynch syndrome (PMID: 30927264). 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: 218051). For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV004003463	SCV004843037	pathogenic	Lynch syndrome	2023-05-03	criteria provided, single submitter	clinical testing	The c.1168del (p.Asp390Ilefs*21) variant in the MSH6 gene is located on the exon 4 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Asp390Ilefs*21), resulting in an absent or disrupted protein product. The variant has been reported in 2 unrelated individuals affected with Lynch syndrome (PMID: 27903930, 30383610). Loss-of-function variants located downstream to this position have been reported in individuals with Lynch syndrome-associated cancer (PMID: 20028993). The variant is rare in the general population according to gnomAD (5/251000). Therefore, the c.1168del (p.Asp390Ilefs*21) variant of MSH6 has been classified as pathogenic.
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV005239092	SCV005882930	pathogenic	Inherited MMR deficiency (Lynch syndrome)	2024-10-17	criteria provided, single submitter	clinical testing	PVS1,PP4_Moderate