Submissions for variant NM_000179.3(MSH6):c.1691C>A (p.Ser564Ter)

dbSNP: rs864622153

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204908	SCV000259478	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser564*) 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 premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 27601186). 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. ClinVar contains an entry for this variant (Variation ID: 219551). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000481005	SCV000570637	pathogenic	not provided	2017-04-14	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1691C>A at the cDNA level and p.Ser564Ter (S564X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in an individual tested on a hereditary colorectal cancer panel (Ferber 2016). We consider this variant to be pathogenic.
Ambry Genetics	RCV000491176	SCV000580348	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-28	criteria provided, single submitter	clinical testing	The p.S564* pathogenic mutation (also known as c.1691C>A), located in coding exon 4 of the MSH6 gene, results from a C to A substitution at nucleotide position 1691. This changes the amino acid from a serine to a stop codon within coding exon 4. This mutation has been detected in multiple endometrial cancer patients whose tumors demonstrated loss of MSH6 on immunohistochemistry (Ambry internal data). A different nucleotide change at this position (c.1691C>G) that leads to the same stop codon was seen in two Swedish families with Lynch syndrome (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835). 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.
Counsyl	RCV000576302	SCV000677830	likely pathogenic	Lynch syndrome 5	2016-12-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491176	SCV000690217	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-01	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 been observed in an individual affected with ovarian cancer (Color internal data). A different DNA substitution resulting in the same protein consequence (c.1691C>G; p.Ser564*) has been observed in two families affected with Lynch syndrome (PMID: 27601186). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481005	SCV000888247	pathogenic	not provided	2018-01-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576302	SCV004018900	pathogenic	Lynch syndrome 5	2023-03-28	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.
PreventionGenetics, part of Exact Sciences	RCV004530217	SCV004121047	pathogenic	MSH6-related disorder	2022-09-21	criteria provided, single submitter	clinical testing	The MSH6 c.1691C>A variant is predicted to result in premature protein termination (p.Ser564*). This variant has been reported in an individual being tested on a hereditary colorectal cancer panel (Ferber et al. 2016. Journal of Medical Diagnostic Methods, vol 5). A different nucleotide variant (c.1691C>G) which also causes a premature termination codon at this position has been reported in individuals with Lynch syndrome (Lagerstedt-Robinson et al. 2016. PubMed ID: 27601186). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in MSH6 are expected to be pathogenic. Given the evidence, we interpret c.1691C>A (p.Ser564*) as pathogenic.
CZECANCA consortium	RCV001270947	SCV001451751	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing