Submissions for variant NM_000251.3(MSH2):c.2211-10T>A

dbSNP: rs267608006

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000791387	SCV000260343	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 13 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 90927). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000478566	SCV000569683	likely pathogenic	not provided	2022-06-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 17199584)
Ambry Genetics	RCV000491555	SCV000580509	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-15	criteria provided, single submitter	clinical testing	The c.2211-10T>A intronic variant results from a T to A substitution 10 nucleotides upstream from coding exon 14 in the MSH2 gene. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC); however, this variant has also been identified in a proband who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated loss of MSH2/MSH6 expression by IHC (Ambry internal data). In addition, this variant has been identified in multiple probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH2/MSH6 expression by IHC (interlaboratory communication, Ambry internal data). This variant has been reported in a patient diagnosed with Muir-Torre syndrome whose personal history consisted of colorectal cancer at the age of 47 and prostate cancer, melanoma, and a sebaceous adenoma all at the age of 68. Tumor IHC analysis showed the absence of MSH2 and MSH6. The patient's family history of cancer consisted of a brother diagnosed with colorectal cancer at the age of 54, a father diagnosed with colorectal cancer at an unknown age, and a mother diagnosed with esophageal cancer at an unknown age (Mangold et al. Br J Dermatol. 2007 Jan;156(1):158-62). This nucleotide position is well 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491555	SCV000903947	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This variant causes a T to A nucleotide substitution at the -10 position of intron 13 of the MSH2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Lynch syndrome-associated cancers (communication with external laboratories; ClinVar SCV000580509.6, SCV000260343.7). This variant has also been reported in the literature in an individual affected with Muir-Torre syndrome with a family history of colorectal and esophageal cancer, and the proband's tumor showed lack of MSH2 and MSH6 protein expression (PMID: 17199584). This variant has been identified in 1/251118 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Baylor Genetics	RCV003460716	SCV004196919	likely pathogenic	Lynch syndrome 1	2022-01-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997160	SCV004822612	likely pathogenic	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This variant causes a T to A nucleotide substitution at the -10 position of intron 13 of the MSH2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Lynch syndrome-associated cancers (communication with external laboratories; ClinVar SCV000580509.6, SCV000260343.7). This variant has also been reported in the literature in an individual affected with Muir-Torre syndrome with a family history of colorectal and esophageal cancer, and the proband's tumor showed lack of MSH2 and MSH6 protein expression (PMID: 17199584). This variant has been identified in 1/251118 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.