Submissions for variant NM_000179.3(MSH6):c.2550C>G (p.Tyr850Ter)

dbSNP: rs374230313

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000469257	SCV000551175	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-07-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 410471). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr850*) 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).
Ambry Genetics	RCV000566681	SCV000673931	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-29	criteria provided, single submitter	clinical testing	The p.Y850* pathogenic mutation (also known as c.2550C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2550. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. A different alteration resulting in the same stop codon (c.2550C>A) has been reported in 2 individuals from a cohort of individuals undergoing multigene panel testing (Espenschied CR et al. J. Clin. Oncol., 2017 Aug;35:2568-2575). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Color Diagnostics, LLC DBA Color Health	RCV000566681	SCV001347281	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 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 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.
Myriad Genetics, Inc.	RCV003449149	SCV004185658	pathogenic	Lynch syndrome 5	2023-08-17	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
All of Us Research Program, National Institutes of Health	RCV004001837	SCV004842626	pathogenic	Lynch syndrome	2023-11-13	criteria provided, single submitter	clinical testing	The c.2550C>G (p.Tyr850*) variant in the MSH6 gene is located on the exon 4 and introduces a premature translation termination codon (p.Tyr850*), resulting in an absent or disrupted protein product. Alternative variant causing protein truncation at the same position (c.2550C>A, p.Tyr850*, ClinVar ID: 186657) has been reported in 2 individuals with Lynch syndrome-associated cancer (PMID: 28514183). Loss-of-function variants of MSH6 are known to be pathogenic and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with Lynch syndrome-associated cancers (PMID: 30376427, 18269114, 29345684). The variant is reported in ClinVar (ID: 410471). The variant is absent in the general population database (gnomAD). Therefore, the c.2550C>G (p.Tyr850*) variant of MSH6 has been classified as pathogenic.
Laboratory for Genotyping Development, RIKEN	RCV003168831	SCV002758542	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV003483627	SCV004228540	not provided	Lynch syndrome; Mismatch repair cancer syndrome 3		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 12-01-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.