Submissions for variant NM_000179.3(MSH6):c.706_707del (p.Gln236fs)

dbSNP: rs1553412129

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581631	SCV000690473	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-27	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides 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 hereditary cancer 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	RCV000629675	SCV000750631	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln236Argfs*3) 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. 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000581631	SCV001188278	pathogenic	Hereditary cancer-predisposing syndrome	2018-06-07	criteria provided, single submitter	clinical testing	The c.706_707delCA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 706 to 707, causing a translational frameshift with a predicted alternate stop codon (p.Q236Rfs*3). 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.
Division of Medical Genetics, University of Washington	RCV001250433	SCV001424803	pathogenic	Lynch syndrome 5	2019-07-12	criteria provided, single submitter	clinical testing	The c.706_707delCA variant results in a two nucleotide deletion that causes a shift in the reading frame and ultimately leads to a premature stop codon. This variant has not been reported in the gnomAD database. Two laboratories have reported this variant in the ClinVar database, both of which classified it as pathogenic. To our knowledge, this sequence variant has not been previously reported in the medical literature; however, haploinsufficiency of the MSH6 gene is a known mechanism of disease. Based on the available information we interpret the c.706_707delCA variant as pathogenic.
GeneDx	RCV002508234	SCV002817672	pathogenic	not provided	2022-06-27	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; Has not been previously published as pathogenic or benign to our knowledge
Myriad Genetics, Inc.	RCV001250433	SCV004185889	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.