ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2248T>C (p.Leu750=) (rs527725593)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000587617 SCV000260116 likely benign not provided 2019-01-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562101 SCV000662253 likely benign Hereditary cancer-predisposing syndrome 2016-06-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Synonymous alterations with insufficient evidence to classify as benign
Color RCV000562101 SCV000685027 likely benign Hereditary cancer-predisposing syndrome 2017-02-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587617 SCV000696242 likely benign not provided 2017-03-30 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2248T>C (p.Leu750Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not significantly affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC in 6 of 121332 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.000303 (5/16500). This frequency is nearly equivalent to the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is may be a benign polymorphism found primarily in the populations of South Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.

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