Submissions for variant NM_000179.3(MSH6):c.3716_3717del (p.Ile1239fs)

dbSNP: rs1064794384

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482291	SCV000569026	pathogenic	not provided	2015-12-21	criteria provided, single submitter	clinical testing	This deletion of 2 nucleotides in MSH6 is denoted c.3716_3717delTA at the cDNA level and p.Ile1239LysfsX35 (I1239KfsX35) at the protein level. The normal sequence, with the bases that are deleted in braces, is ACTA[TA]AAAT. The deletion causes a frameshift, which changes an Isoleucine to a Lysine at codon 1239, and creates a premature stop codon at position 35 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Ambry Genetics	RCV000561455	SCV000673947	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-22	criteria provided, single submitter	clinical testing	The c.3716_3717delTA pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3716 to 3717, causing a translational frameshift with a predicted alternate stop codon (p.I1239Kfs*35). This alteration was identified in a cohort of women undergoing multigene panel testing for hereditary cancer risk (Roberts ME et al. Genet Med, 2018 10;20:1167-1174). 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.
Invitae	RCV000697841	SCV000826473	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-10	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This sequence change creates a premature translational stop signal (p.Ile1239Lysfs*35) 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). ClinVar contains an entry for this variant (Variation ID: 420268). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482291	SCV000889491	pathogenic	not provided	2018-06-11	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002466516	SCV002761603	pathogenic	Lynch syndrome 5	2022-04-29	criteria provided, single submitter	clinical testing	The MSH6 c.3716_3717del variant is classified as Likely Pathogenic (PVS1, PM2) This MSH6 c.3716_3717del variant is located in exon 8/10 and is predicted to cause a shift in the reading frame at codon 1239. This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs1064794384) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 420268). It has not been reported in HGMD.
Myriad Genetics, Inc.	RCV002466516	SCV004185623	pathogenic	Lynch syndrome 5	2023-08-25	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	RCV003464010	SCV004196366	likely pathogenic	Endometrial carcinoma	2021-07-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000561455	SCV004357747	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-31	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 8 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. This variant has been reported in an individual undergoing genetic testing for Lynch syndrome and colorectal cancer (PMID: 29345684). This individual had a personal history of breast cancer. 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.
All of Us Research Program, National Institutes of Health	RCV004003322	SCV004827565	pathogenic	Lynch syndrome	2023-05-31	criteria provided, single submitter	clinical testing	The c.3716_3717del (p.Ile1239Lysfs*35) variant in the MSH6 gene is located on the exon 8 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Ile1239Lysfs*35), resulting in an absent or disrupted protein product. The variant has been identified in an individual with breast cancer (PMID: 29345684). Loss-of-function variants in MSH6 are known to be pathogenic and frameshift/truncating variants located downstream to this position have been reported in individuals with Lynch syndrome-associated cancers (PMID: 20028993, 18269114). The variant is reported in ClinVar (ID: 420268). This variant is absent in the general population database (gnomAD). Therefore, the c.3716_3717del (p.Ile1239Lysfs*35) variant of MSH6 has been classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000482291	SCV000778624	likely pathogenic	not provided	2018-02-20	no assertion criteria provided	clinical testing
Gharavi Laboratory, Columbia University	RCV000482291	SCV000809467	pathogenic	not provided	2018-09-16	no assertion criteria provided	research