Submissions for variant NM_000251.3(MSH2):c.399C>T (p.Asp133=)

gnomAD frequency: 0.00003  dbSNP: rs61756462

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164131	SCV000214746	likely benign	Hereditary cancer-predisposing syndrome	2019-10-28	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	RCV000524407	SCV000559229	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000608950	SCV000728921	benign	not specified	2015-04-29	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.
Counsyl	RCV000663052	SCV000786102	uncertain significance	Lynch syndrome 1	2018-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164131	SCV000910871	likely benign	Hereditary cancer-predisposing syndrome	2016-04-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663052	SCV004018382	benign	Lynch syndrome 1	2023-03-22	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.
PreventionGenetics, part of Exact Sciences	RCV004542748	SCV004777850	likely benign	MSH2-related disorder	2022-02-25	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	RCV003997173	SCV004830177	likely benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357112	SCV001552466	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Asp133= variant was identified in 4 of 5920 proband chromosomes (frequency: 0.0007) from individuals or families with HNPCC (Grabowski 2004, Mangold 2005, Samowitz 2001, Woods 2005). The variant was also identified in dbSNP (ID: rs61756462) as "With Uncertain significance allele", ClinVar (classified as benign by GeneDx; as likely benign by Invitae; as uncertain significance by two submitters), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (7x). The variant was not identified in COGR, Cosmic, MutDB, UMD-LSDB, or Zhejiang University databases. The variant was identified in control databases in 5 of 277186 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 5 of 126684 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asp133= 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) do not predict a difference in splicing. In addition, the variant was found co-occurring with pathogenic mutation (Mangold 2005). 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.