Submissions for variant NM_000251.3(MSH2):c.1560A>G (p.Gly520=)

gnomAD frequency: 0.00007  dbSNP: rs63750820

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212603	SCV000170339	benign	not specified	2014-01-24	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.
Ambry Genetics	RCV000126813	SCV000213544	benign	Hereditary cancer-predisposing syndrome	2022-06-23	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000524346	SCV000253150	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000662509	SCV000430925	uncertain significance	Lynch syndrome 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000126813	SCV000537417	likely benign	Hereditary cancer-predisposing syndrome	2015-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212603	SCV000696217	likely benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000662509	SCV000785045	likely benign	Lynch syndrome 1	2017-03-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212603	SCV001469554	benign	not specified	2019-11-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001815198	SCV002063855	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MSH2: BP4, BP7
Sema4, Sema4	RCV000126813	SCV002534379	likely benign	Hereditary cancer-predisposing syndrome	2020-06-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212603	SCV002552234	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662509	SCV004018289	benign	Lynch syndrome 1	2023-03-20	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492569	SCV004239271	likely benign	Breast and/or ovarian cancer	2022-11-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532521	SCV004716523	likely benign	MSH2-related disorder	2020-08-24	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).
All of Us Research Program, National Institutes of Health	RCV003997440	SCV004831680	likely benign	Lynch syndrome	2024-01-03	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356577	SCV001551786	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Gly520= variant was identified in 1 of 3786 proband chromosomes (frequency: 0.0003) from individuals or families with ovarian cancer (Pal 2012). The variant was also identified in dbSNP (ID: rs63750820) as “With other allele”, ClinVar (classified as benign by GeneDx and Invitae, as likely benign by Ambry Genetics and Color Genomics, and as uncertain significance by Illumina Clinical Services), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database (1x). The variant was not identified in COGR, COSMIC, MutDB, UMD-LSDB, or Zhejiang Colon Cancer databases. The variant was identified in control databases in 34 of 277178 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Ashkenazi Jewish in 29 of 10150 chromosomes (freq: 0.003), Other in 3 of 6464 chromosomes (freq: 0.0005), and European in 2 of 126680 chromosomes (freq: 0.00002), while the variant was not observed in the African, Latino, East Asian, Finnish, or South Asian populations. In an in vitro study of mismatch repair efficiency, this variant demonstrated in tact MMR activity (Tronov 2006). The p.Gly520= 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, 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, Human Splicing Finder) predict that the variants creates a new 5’ splice site. 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.