Submissions for variant NM_000251.3(MSH2):c.226C>T (p.Gln76Ter)

dbSNP: rs63750042

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076447	SCV000107476	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Invitae	RCV000684780	SCV000548220	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-08	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: 90945). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and/or mediastinal T-cell non-Hodgkin lymphoma (PMID: 16034045, 17601929, 19669601, 20587412, 22480969, 28874130). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln76*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816).
GeneDx	RCV000202307	SCV000568620	pathogenic	not provided	2018-10-12	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.226C>T at the cDNA level and p.Gln76Ter (Q76X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in several individuals meeting Amsterdam II Criteria or Bethesda Guidelines for Lynch syndrome (Stormorken 2005, Sjursen 2010, Bonnet 2012). MSH2 Gln76Ter was also observed in multiple members of a large Kuwaiti family meeting Amsterdam Criteria; three members of this family presented in childhood with lymphoma and café-au-lait macules, and two of these children were confirmed to be homozygous for this variant (Scott 2007, Marafie 2009). Results from several functional assays in cells homozygous for MSH2 Gln76Ter were consistent with observations from MSH2 knockout mice, which have demonstrated reduced RAD51 loci and increased chromosome damage after ionizing radiation (Barwell 2007). This variant is considered pathogenic.
Ambry Genetics	RCV000491576	SCV000580495	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-11	criteria provided, single submitter	clinical testing	The p.Q76* pathogenic mutation (also known as c.226C>T), located in coding exon 2 of the MSH2 gene, results from a C to T substitution at nucleotide position 226. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This alteration has been reported in a patient diagnosed with colorectal cancer at age 59 whose tumor showed absent staining for the MSH2 protein via immunohistochemistry (Stormorken A et al. J. Clin. Oncol. 2005 Jul;23(21):4705-12). It has also been reported in two large and highly consanguineous families in Kuwait who meet Amsterdam criteria (Marafie MJ et al. Fam. Cancer 2009;8(4):289-98). In one of these families, three siblings who were homozygous for this alteration developed non-Hodgkin lymphoma and pigmentary skin abnormalities in early childhood, consistent with a diagnosis of constitutional mismatch repair-deficiency (CMMR-D) syndrome; their parents, who were first cousins, were presymptomatic heterozygous carriers of this alteration (Scott RH et al. J. Med. Genet. 2007 Jul;44(7):e83). 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003312993	SCV004011720	pathogenic	Lynch syndrome 1	2023-07-10	criteria provided, single submitter	clinical testing	The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon, and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in several individuals with Lynch syndrome (Stormorken 2005, Sjursen 2010, Bonnet 2012). MSH2 Gln76Ter was also observed in multiple members of a large Kuwaiti family meeting Amsterdam Criteria; three members of this family presented in childhood with lymphoma, and two of these children were confirmed to be homozygous for this variant (Scott 2007, Marafie 2009). This variant is considered pathogenic.
Myriad Genetics, Inc.	RCV003312993	SCV004187934	pathogenic	Lynch syndrome 1	2023-07-26	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202307	SCV000257172	pathogenic	not provided		no assertion criteria provided	research
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001250039	SCV001423964	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing