Submissions for variant NM_000251.3(MSH2):c.1690A>G (p.Thr564Ala)

gnomAD frequency: 0.00008  dbSNP: rs55778204

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076247	SCV000107266	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
Invitae	RCV001081232	SCV000166266	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000589504	SCV000515767	likely benign	not provided	2020-10-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22290698, 15996210, 24362816, 12200596, 18726168, 24735542, 17192056, 25980754, 24710284, 26900293, 29506494)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000445069	SCV000539681	likely benign	not specified	2016-12-02	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in 0.25% of East Asian chrs (0.31% in gnomAD - too high for disease frequency). It is classified in ClinVar with 3 stars as benign by an expert panel (InSiGHT) and Invitae. It has been reported in 3 papers: in one it did not segregate in the family with disease, in one it was predicted to be not pathogenic, and one where MSH2 expression was retained. Rabbit also has an Alanine at this position.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589504	SCV000601436	benign	not provided	2019-07-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564309	SCV000662216	likely benign	Hereditary cancer-predisposing syndrome	2018-12-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589504	SCV000696223	benign	not provided	2017-02-02	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.1690A>G (p.Thr564Ala) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO and Mutation Taster not captured due to low reliability index). This variant was found in 22/120830 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.002547 (22/8638). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant was found in several studies assessing colorectal cancer patients with normal IHC and microsatellite stable tumors; however no strong evidence for pathogenicity were present. Furthermore, in one family the variant did not co-segregate with the disease, and the cause of cancer in this family was attributed to a pathogenic variant in the APC gene, further supporting a neutral outcome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Considering all evidence, the variant is classified as Benign.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659881	SCV000781773	uncertain significance	Lynch syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564309	SCV000910721	likely benign	Hereditary cancer-predisposing syndrome	2015-11-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000659881	SCV001135741	benign	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000564309	SCV002534397	likely benign	Hereditary cancer-predisposing syndrome	2021-06-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000445069	SCV002552238	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504985	SCV002808530	likely benign	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2022-03-08	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492422	SCV004239274	likely benign	Breast and/or ovarian cancer	2022-10-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537291	SCV004753223	likely benign	MSH2-related disorder	2019-06-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355421	SCV001550302	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Thr564Ala variant was identified in 8 of 468 proband chromosomes (frequency: 0.02) from Chinese and Taiwanese individuals or families with HNPCC/suspected HNPCC related CRC (Chang_2016_26900293, Lee_2005_15996210, Yap_2009_18726168). In a 4 generation Han Chinese family affected with polyposis, sequencing of 5 genes related to HNPCC/FAP found the variant to co-occur with a truncating APC variant (c.694C>), and the variant was found in both affected and unaffected members (Zhang_2014_24735542). Two bioinformatics prediction models pathogenic-or-not mismatch repair (PONMMR), and multivariate analysis of protein polymorphisms–mismatch repair (MAPP-MMR) assessed the variant as neutral (Ali_2012_22290698, Chao_2008_18383312). The variant was also identified in dbSNP (ID: rs55778204) “With Likely benign allele”, ClinVar (classified benign, reviewed by an expert panel (2013); submitters: benign by InSIGHT, and likely benign by Invitae, GeneDx, Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (2x), Insight Colon Cancer Gene Variant Database (13x as class 1), Zhejiang Colon Cancer Database (2x), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (14x), and was not identified in GeneInsight-COGR, Cosmic, MutDB, or UMD-LSDB. The variant was identified in control databases in 59 of 276412 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 59 of 18860 chromosomes (freq: 0.003), while not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Thr564 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of the variant Ala impacting the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.