Submissions for variant NM_000179.3(MSH6):c.642C>G (p.Tyr214Ter)

dbSNP: rs1800937

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075016	SCV000108236	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000485263	SCV000567945	pathogenic	not provided	2021-11-29	criteria provided, single submitter	clinical testing	Nonsense 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 (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Verma 1999, Murphy 2008, Pritchard 2016); This variant is associated with the following publications: (PMID: 25525159, 27433846, 25871441, 10507723, 18409202, 18709565, 21376568, 21674763, 18236172, 17259933, 27806231, 33087929)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703480	SCV000832383	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr214*) 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 colorectal cancer and metastatic prostate cancer and constitutional mismatch repair-deficiency (PMID: 10507723, 17259933, 27433846). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 89547). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001025256	SCV001187409	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-01	criteria provided, single submitter	clinical testing	The p.Y214* pathogenic mutation (also known as c.642C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 642. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. This alteration, described as C642G (Tyr214Ter), was detected in a proband with colorectal cancer diagnosed at age 43 whose tumor was MSI-H (Verma L et al. J. Med. Genet., 1999 Sep;36:678-82). This alteration has also been detected in the compound heterozygous state in a child with a personal history of hyperpigmented and hypopigmented skin lesions, IgA and IgG2 deficiencies, medulloblastoma diagnosed at age 7, acute myelocytic leukemia diagnosed at age 10 and two colonic carcinomas diagnosed at age 13 (Scott RH et al. Nat Clin Pract Oncol, 2007 Feb;4:130-4). It has been identified in a patient with a history of sebaceous adenomas, testicular embryonal teratoma and adenomatous colon polyps with a family history of gastrointestinal malignancies (Murphy HR et al. Fam. Cancer, 2008 Jan;7:255-7). This alteration was also identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med., 2016 Aug;375:443-53). 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.
Fulgent Genetics, Fulgent Genetics	RCV002477214	SCV002779274	pathogenic	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-04-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450990	SCV004185592	pathogenic	Lynch syndrome 5	2023-08-10	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000075016	SCV004848288	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Tyr214X variant in MSH6 has been previously reported in the heterozygous state in at least 1 individual with colorectal cancer (Verma 1999), 1 individual with metastatic prostate cancer (Pritchard 2016), and 1 individual with multiple sebaceous adenomas/embryonal teratoma of the testis and family history of gastrointestinal cancers (Murphy 2008), and in the compound heterozygous state in 1 individual with constitutional mismatch repair-deficiency (Scott 2007). It was absent from large population studies. This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89547). This nonsense variant leads to a premature termination codon at position 214, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting, PM3.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000485263	SCV001931260	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000485263	SCV001958322	pathogenic	not provided		no assertion criteria provided	clinical testing