Submissions for variant NM_000251.2(MSH2):c.2458+4T>C (rs1038735071)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000431124	SCV000527911	likely benign	not specified	2016-12-30	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	RCV000574853	SCV000669797	uncertain significance	Hereditary cancer-predisposing syndrome	2016-12-09	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Invitae	RCV000630059	SCV000751015	uncertain significance	Hereditary nonpolyposis colon cancer	2018-12-16	criteria provided, single submitter	clinical testing	This sequence change falls in intron 14 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 386321). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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