Submissions for variant NM_000251.3(MSH2):c.1662-10C>T

gnomAD frequency: 0.00008  dbSNP: rs752606387

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001083456	SCV000559186	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580913	SCV000684960	likely benign	Hereditary cancer-predisposing syndrome	2016-04-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590414	SCV000696221	uncertain significance	not provided	2017-06-05	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.1662-10C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in ExAC and the literature in 33/118436 control chromosomes at a frequency of 0.0002786, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). However, one publication reported that the variant is a common polymorphism in black South African controls (frequency = 0.34) suggesting the variant is benign (Davison_Dissertation_2012). In addition, one clinical diagnostic laboratory has classified this variant as likely benign. Taken together, this variant is classified as VUS-possibly benign.
GeneDx	RCV000590414	SCV001745401	benign	not provided	2015-03-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150227	SCV003838304	uncertain significance	Breast and/or ovarian cancer	2022-06-17	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000590414	SCV001552910	likely benign	not provided		no assertion criteria provided	clinical testing	The MSH2 c.1662-10C>T variant was not identified in the literature nor was it identified in the UMD-LSDB, database. The variant was identified in dbSNP (ID: rs752606387) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Color Genomics; classified as uncertain significance by Integrated Genetics/Laboratory Corporation of America). The variant was identified by our laboratory in a patient with breast cancer under the age of 30 and a co-occurring BRCA1 pathogenic variant (BRCA1, c.1100del). The variant was identified in control databases in 7 of 276086 chromosomes at a frequency of 0.000025 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23982 chromosomes (freq: 0.00004), European Non-Finnish in 5 of 126050 chromosomes (freq: 0.00004), and South Asian in 1 of 30530 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or European Finnish populations. The variant occurs outside of the splicing consensus sequence and 0 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The MSH2 c.1662-10C nucleotide is not conserved in mammals and a C>T substitution is observed in several species. 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.