Submissions for variant NM_000251.3(MSH2):c.970C>T (p.Gln324Ter)

dbSNP: rs63750502

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076766	SCV000107807	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV001019659	SCV001181046	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	clinical testing	The p.Q324* pathogenic mutation (also known as c.970C>T), located in coding exon 6 of the MSH2 gene, results from a C to T substitution at nucleotide position 970. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This mutation has been previously reported in French patients with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13; Bonadona V et al. JAMA, 2011 Jun;305:2304-10). This mutation was also seen in patients who met Amsterdam criteria with MSI-H colorectal cancers demonstrating absent staining of MSH2 on immunohistochemistry (Bécouarn Y et al. Gastroenterol. Clin. Biol. 2005;29:667-75; Paraf F et al. Histopathology, 2001 Sep;39:250-8). One woman from a family with urinary tract cancers was also found to have this mutation (Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199). 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.
Invitae	RCV001050003	SCV001214089	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-30	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: 91261). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 16142001). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln324*) 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).
Revvity Omics, Revvity	RCV000201985	SCV003822172	pathogenic	not provided	2022-04-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003452980	SCV004188136	pathogenic	Lynch syndrome 1	2023-07-28	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000201985	SCV000257201	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000201985	SCV001552468	pathogenic	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Gln324* variant was identified in the literature in an individual with low grade serous carcinoma of the ovary, however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs63750502) as “with pathogenic allele”, ClinVar (2x as pathogenic by InSiGHT and Mayo), Cosmic (as pathogenic), UMD-LSDB (11x as causal), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database (as pathogenic). The variant was not identified in GeneInsight-COGR, MutDB, Insight Colon Cancer Gene Variant Database, and Zhejiang Colon Cancer Database. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) or in the Genome Aggregation Consortium (February 27, 2017) control databases. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The c.970C>T variant leads to a premature stop codon at position 324, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.