Submissions for variant NM_000251.3(MSH2):c.471C>A (p.Gly157=)

gnomAD frequency: 0.00029  dbSNP: rs61756463

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076604	SCV000107640	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Synonymous substitution with no effect on splicing & MAF 0.01-1%
GeneDx	RCV000212586	SCV000170348	benign	not specified	2014-04-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CSER _CC_NCGL, University of Washington	RCV000076604	SCV000212176	likely benign	Lynch syndrome	2015-03-11	criteria provided, single submitter	research
Ambry Genetics	RCV000126822	SCV000212810	likely benign	Hereditary cancer-predisposing syndrome	2014-07-16	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.
Invitae	RCV001079841	SCV000252656	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000126822	SCV000685094	benign	Hereditary cancer-predisposing syndrome	2015-11-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586050	SCV000696270	benign	not provided	2016-06-20	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.471C>A (p.Gly157Gly) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 132/121410 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0146753 (127/8654). This frequency is about 26 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. This variant has been reported in multiple affected individuals and all are East Asians. The studies reporting this variant mostly detected variant in controls with higher or comparable MAF as in case cohorts. In addition, variant was detected to co-occur with a likely disease variant (c.-80insA) that can explain the disease phenotype, further supporting the benign classification of this variant. Multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625237	SCV000744268	likely benign	Lynch syndrome 1	2017-06-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000212586	SCV000806043	benign	not specified	2017-06-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625237	SCV001297029	likely benign	Lynch syndrome 1	2018-10-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000212586	SCV002070915	benign	not specified	2020-04-20	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212586	SCV002760632	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000625237	SCV004015954	likely benign	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586050	SCV004699059	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	MSH2: BP4, BP7, BS1
Mayo Clinic Laboratories, Mayo Clinic	RCV000212586	SCV000691897	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625237	SCV000745633	benign	Lynch syndrome 1	2016-07-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355755	SCV001550723	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Gly157= variant was identified in 8 of 1390 proband chromosomes (frequency: 0.006) from individuals or families with Lynch syndrome and or sporadic CRC (Nomura 2000, Shin 2004, Chang 2016, Hu 2013). The variant was also identified in the following databases: dbSNP (ID: rs61756463) as “With Likely benign allele”, ClinVar (3x, as likely benign by InSight, Ambry Genetic, University of Washington and 2x, as benign by GeneDx, Invitae with expert panel review), Clinvitae (3x, as benign and likely benign), Insight Colon Cancer Gene Variant Database (4x, as class 2 ), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (4x, as class 2). The variant was not identified in Cosmic, MutDB, UMD-LSDB and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 270 of 277200 chromosomes at a frequency of 0.000974 in the following populations: other in 6 of 6468 chromosomes (freq. 0.0009), Latino in 1 of 34420 chromosomes (freq. 0.00003), European in 1 of 126700 chromosomes (freq. 0.000008), East Asian in 253 of 18862 chromosomes (freq. 0.013), and South Asian in 9 of 30786 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The c.471C>A is reported as polymorphism in the MSH2 gene and showed no significant association with Lynch syndrome, suspected lynch syndrome, or early-onset CRC patients in Korean cohort (Shin 2004).The p.Gly157= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000212586	SCV001921799	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000212586	SCV002036360	benign	not specified		no assertion criteria provided	clinical testing