Submissions for variant NM_000251.3(MSH2):c.211+8C>T

gnomAD frequency: 0.00003  dbSNP: rs267607916

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427874	SCV000513648	benign	not specified	2015-08-15	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.
Invitae	RCV001085835	SCV000559218	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579968	SCV000685010	likely benign	Hereditary cancer-predisposing syndrome	2015-11-12	criteria provided, single submitter	clinical testing
Counsyl	RCV000663062	SCV000786123	likely benign	Lynch syndrome 1	2018-02-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759110	SCV000888216	likely benign	not provided	2022-04-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000427874	SCV000917711	uncertain significance	not specified	2018-01-12	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.211+8C>T variant involves the alteration of a non-conserved intronic nucleotide and 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts the elimination of ESE binding sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 10/242066 control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000092 (10/108416). This frequency does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). Multiple clinical diagnostic laboratories classified this variant as "likely benign/benign." The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance - Possibly Benign," until additional information becomes available.
CeGaT Center for Human Genetics Tuebingen	RCV000759110	SCV001152270	likely benign	not provided	2022-10-01	criteria provided, single submitter	clinical testing	MSH2: BP4, BS2
Myriad Genetics, Inc.	RCV000663062	SCV004018211	benign	Lynch syndrome 1	2023-03-16	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
PreventionGenetics, part of Exact Sciences	RCV003950357	SCV004767090	likely benign	MSH2-related condition	2019-07-16	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000759110	SCV001549862	likely benign	not provided		no assertion criteria provided	clinical testing	The MSH2 c.211+8C>T variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs267607916) as “with likely benign, uncertain significance allele” and ClinVar (classified as likely benign by Invitae, Counsyl, Color and Quest Diagnostics, benign by GeneDx and uncertain significance by Integrated Genetics). The variant was identified in control databases in 10 of 246,872 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 10 of 111,074 chromosomes (freq: 0.00009), but not in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. The variant occurs at a weakly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.