Submissions for variant NM_000251.3(MSH2):c.1662-2A>G

dbSNP: rs267607971

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076225	SCV000107249	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Invitae	RCV000560516	SCV000625295	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-09-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1662-2A nucleotide in the MSH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18566915, 24090359). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 90728). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 16810763, 21642682). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 10 of the MSH2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526860	SCV000919688	pathogenic	Hereditary nonpolyposis colon cancer	2021-05-24	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1662-2A>G 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: Two predict that the variant abolishes a 3-prime acceptor site. One predicts that the variant creates a 5-prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250122 control chromosomes. c.1662-2A>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Wang_2006, Bonadona_2011, Rossi_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two otherClinVar submitters (evaluation after 2014), including one expert panel, have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002399456	SCV002706543	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-28	criteria provided, single submitter	clinical testing	The c.1662-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 11 in the MSH2 gene. This variant was detected in 1/537 French families tested for Lynch syndrome (Bonadona V et al. JAMA, 2011 Jun;305:2304-10). This variant was also reported in Argentinian Lynch syndrome family (Rossi BM et al. BMC Cancer, 2017 Sep;17:623). In addition, this variant was identified in conjunction (phase unknown) with a truncating pathogenic MSH2 mutation, c.1665del (p.Lys555Asnfs*2), in a Chinese hereditary nonpolyposis colorectal cancer family (Wang XL et al. World J Gastroenterol, 2006 Jul;12:4074-7). Furthermore, this variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated loss of MSH2/MSH6 expression by immunohistochemistry (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 acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.