Submissions for variant NM_000251.2(MSH2):c.1386+1G>A (rs267607957)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076137	SCV000107152	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Invitae	RCV000684786	SCV000253799	pathogenic	Hereditary nonpolyposis colon cancer	2019-11-13	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic. This particular variant has been reported in the literature in two individuals affected with Lynch syndrome (PMID: 15849733). Experimental studies have shown that this variant leads to exclusion of exon 8 from the MSH2 transcript (PMID: 16395668, 19669161). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491969	SCV000580476	pathogenic	Hereditary cancer-predisposing syndrome	2018-10-03	criteria provided, single submitter	clinical testing	Functionally-validated splicing mutation;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000076137	SCV000592500	pathogenic	Lynch syndrome	2014-08-26	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000076137	SCV000696210	pathogenic	Lynch syndrome	2016-05-13	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.1386+1G>A variant involves the alteration of a conserved intronic nucleotide with 5/5 splice prediction tools calculating a significant effect on splicing, which is further supported by functional studies showing an impact on splicing. The variant of interest has not been observed in the general population and has been reported in multiple affected individuals via publications, along with multiple clinical laboratories/databases citing the variant as "likely pathogenic/pathogenic." Therefore, the variant of interest is classified as Pathogenic.

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