Submissions for variant NM_000251.3(MSH2):c.1661+2T>C

dbSNP: rs1553366680

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000559692	SCV000625292	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-11-15	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 10 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 12624141, 16034045, 16142001, 17569143, 21642682). ClinVar contains an entry for this variant (Variation ID: 455513). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and skipping of exon 10 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002404370	SCV002707539	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	clinical testing	The c.1661+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 10 in the MSH2 gene. This variant has been identified in at least one individual whose Lynch syndrome-related tumor demonstrated loss of MSH2 and MSH6 expression by IHC (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509421	SCV002819563	likely pathogenic	Hereditary nonpolyposis colon cancer	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1661+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250972 control chromosomes. To our knowledge, no occurrence of c.1661+2T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003449535	SCV004186947	pathogenic	Lynch syndrome 1	2023-08-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18561205].