Submissions for variant NM_000251.3(MSH2):c.646-13T>C

gnomAD frequency: 0.00001  dbSNP: rs761205332

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521261	SCV000618012	uncertain significance	not provided	2017-03-07	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.646-13T>C or IVS3-13T>C and consists of a T>C nucleotide substitution at the -13 position of intron 3 of the MSH2 gene. This variant is predicted to damage the natural splice acceptor site and possibly cause abnormal splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 c.646-13T>C was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). The thymine (T) nucleotide that is altered is conserved across species. Based on currently available information, it is unclear whether MSH2 c.646-13T>C is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000583363	SCV000690122	likely benign	Hereditary cancer-predisposing syndrome	2017-06-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553591	SCV001774498	uncertain significance	not specified	2021-07-13	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.646-13T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 248130 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.646-13T>C in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV002060268	SCV002438874	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003605	SCV004832346	likely benign	Lynch syndrome	2023-10-23	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356013	SCV001551062	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 c.646-13T>C variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs761205332) as "With Uncertain significance allele", and in ClinVar (classified as likely benign by Color; as uncertain significance by GeneDx). The variant was identified in control databases in 2 of 243768 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 2 of 110570 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.