Submissions for variant NM_000179.3(MSH6):c.2779dup (p.Ile927fs)

gnomAD frequency: 0.00001  dbSNP: rs587782277

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131134	SCV000186066	pathogenic	Hereditary cancer-predisposing syndrome	2013-01-22	criteria provided, single submitter	clinical testing	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	RCV000218611	SCV000279367	pathogenic	not provided	2017-01-10	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in MSH6 is denoted c.2779dupA at the cDNA level and p.Ile927AsnfsX8 (I927NfsX8) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACTT[A]TTAC. The duplication causes a frameshift, which changes an Isoleucine to an Asparagine at codon 927, and creates a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.2779dupA has been identified in an individual undergoing hereditary cancer panel testing (LaDuca 2014). We consider this variant to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131134	SCV000685324	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-27	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 hereditary cancer in the literature. This variant has been identified in 2/250978 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.
Invitae	RCV001237131	SCV001409882	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-02-05	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs763978082, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Ile927Asnfs*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 premature translational stop signal has been observed in individual(s) with clinical indications of hereditary cancer syndromes, such as Lynch syndrome (PMID: 24763289, 27601186). ClinVar contains an entry for this variant (Variation ID: 142168). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000218611	SCV001450179	pathogenic	not provided	2016-05-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000218611	SCV004011165	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	MSH6: PVS1, PM2
Myriad Genetics, Inc.	RCV003453079	SCV004188267	pathogenic	Lynch syndrome 5	2023-08-21	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017416	SCV004848357	likely pathogenic	Lynch syndrome	2020-05-13	criteria provided, single submitter	clinical testing	The p.Ile927AsnfsX8 variant in MSH6 has been reported in 1 individual undergoing familial cancer panel testing (LaDuca 2014). It has also been identified in 0.002% (2/113400) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 927 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2.
CZECANCA consortium	RCV001270948	SCV001451752	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing