ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1284T>C (p.Asp428=) (rs772555970)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163037 SCV000213527 likely benign Hereditary cancer-predisposing syndrome 2015-11-08 criteria provided, single submitter clinical testing
Counsyl RCV000410355 SCV000489673 likely benign Lynch syndrome II 2016-11-03 criteria provided, single submitter clinical testing
Invitae RCV001080702 SCV000555969 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000163037 SCV000689800 likely benign Hereditary cancer-predisposing syndrome 2017-08-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175374 SCV000696104 likely benign not specified 2019-06-06 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1284T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 251332 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1284T>C, has been reported in the literature in one individual affected with epithelial ovarian cancer (Pal_2012). The report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. One co-occurrence with another pathogenic MLH1 variant have been reported (c.1772_1775delATAG , p.Asp591fsX24), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586026 SCV000888175 likely benign not provided 2017-11-02 criteria provided, single submitter clinical testing

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