Submissions for variant NM_000179.3(MSH6):c.1572C>A (p.Tyr524Ter)

dbSNP: rs587779215

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000791425	SCV000551099	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-11-23	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: 410426). 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.Tyr524*) 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	RCV000491224	SCV000580145	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-12	criteria provided, single submitter	clinical testing	The p.Y524* pathogenic mutation (also known as c.1572C>A), located in coding exon 4 of the MSH6 gene, results from a C to A substitution at nucleotide position 1572. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addtion, 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	RCV000523866	SCV000618271	pathogenic	not provided	2021-03-03	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); 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; A different variant resulting in the same premature stop codon, MSH6 c.1572C>G (p.Tyr524Ter), has been reported in association with HNPCC-related cancers (Rubio 2016); This variant is associated with the following publications: (PMID: 24100870, 29345684, 27398995)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000457937	SCV000695787	pathogenic	Lynch syndrome	2016-11-04	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.1572C>A (p.Tyr524X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1784delT/p.Leu595fsX15; c.2230dupG/p.Glu744fsX12; c.2731C>T/p.Arg911X, etc). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121362 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. However, the variant c.1572C>G leading to the same codon change p.Tyr524X in MSH6 is classified as "pathogenic" by InSiGHT, and has been reported in affected individuals. Taken together, according to ACMG guideline, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003449146	SCV004188280	pathogenic	Lynch syndrome 5	2023-08-14	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.
Baylor Genetics	RCV003463929	SCV004196382	likely pathogenic	Endometrial carcinoma	2021-02-19	criteria provided, single submitter	clinical testing