Submissions for variant NM_000179.3(MSH6):c.742del (p.Arg248fs)

gnomAD frequency: 0.00001  dbSNP: rs587781691

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129856	SCV000184673	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-07	criteria provided, single submitter	clinical testing	The c.742delC pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 742, causing a translational frameshift with a predicted alternate stop codon (p.R248Efs*31). This alteration was observed in a colorectal cancer cohort (AlDubayan SH et al. Am. J. Hum. Genet. 2018 Mar;102(3):401-414) and in an individual diagnosed with breast cancer (Lu HM et al. JAMA Oncol, 2019 01;5:51-57). In addition to the clinical data presented in the literature, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477160	SCV000551199	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg248Glufs*31) 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 (rs587781691, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 28514183). 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: 141365). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657423	SCV000779158	pathogenic	not provided	2023-03-17	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Identified in patients with colorectal or breast cancer (AlDubayan et al., 2018; Huang et al., 2018; Lu et al., 2019); This variant is associated with the following publications: (PMID: 28152038, 30787465, 20301390, 24362816, 18269114, 29703791, 30279230, 29478780, 29625052, 29922827, 35070997, 28514183, 30128536)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657423	SCV001470020	pathogenic	not provided	2020-01-08	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824640	SCV002074461	pathogenic	Hereditary nonpolyposis colon cancer	2022-01-29	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.742delC (p.Arg248GlufsX31) 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 251158 control chromosomes. c.742delC has been reported in the literature in individuals affected with Hereditary cancers/colorectal cancers (example, Espenschied_2017, LaDuca_2017, AlDubayan_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
Sema4, Sema4	RCV000129856	SCV002536353	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-17	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003453070	SCV004188242	pathogenic	Lynch syndrome 5	2023-08-10	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	RCV003467122	SCV004195822	pathogenic	Endometrial carcinoma	2023-03-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997531	SCV004843548	pathogenic	Lynch syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals affected with breast, colorectal, and unspecified cancers (PMID: 29478780, 29625052, 30128536, 35070997). This variant has been identified in 2/282566 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.