Submissions for variant NM_000179.3(MSH6):c.3850dup (p.Thr1284fs)

dbSNP: rs1553333421

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000583214	SCV000690414	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-01	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 9 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.
GeneDx	RCV000657421	SCV000779156	pathogenic	not provided	2023-10-16	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 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; This variant is associated with the following publications: (PMID: 31447099, 31589614)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657421	SCV000889497	likely pathogenic	not provided	2017-12-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501318	SCV000917748	likely pathogenic	Lynch syndrome	2017-12-01	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.3850dupA (p.Thr1284AsnfsX5) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. A variant that affects the same codon and leads to an equivalent change at the protein level (c.3847_3850dupATTA (p.Thr1284Asnfs)) as the variant of interest has been classified as pathogenic by multiple laboratories. Also, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3938_3941dupTTCA (p.Gln1314fsX6), c.3939_3957dupTCAAAAGGGACATAGAAAA (p.Ala1320fsX5), c.3939_3940dupTC (p.Gln1314fsX14)). This variant is absent in 276776 control chromosomes. In addition, one diagnostic laboratory classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Invitae	RCV001380321	SCV001578324	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1284Asnfs*5) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 433926). This variant has not been reported in the literature in individuals affected with MSH6-related conditions.
Ambry Genetics	RCV000583214	SCV002625878	pathogenic	Hereditary cancer-predisposing syndrome	2019-09-23	criteria provided, single submitter	clinical testing	The c.3850dupA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of A at nucleotide position 3850, causing a translational frameshift with a predicted alternate stop codon (p.T1284Nfs*5). 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.
Myriad Genetics, Inc.	RCV003449411	SCV004188194	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353784	SCV000592657	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Thr1284AsnfsX5 variant was not identified in the literature nor was it identified in the dbSNP, Clinvitae, COSMIC, Mismatch Repair Genes Variant, MMR Gene Unclassified Variants, InSiGHT Colon Cancer Gene Variant (LOVD), Zhejiang Colon Cancer (LOVD), ClinVar, GeneInsight - COGR and UMD databases. The variant was also not identified in the 1000 Genomes Project, NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium database (August 8, 2016). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The c.3850dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1284 and leads to a premature stop codon 5 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.