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 RCV000586026 SCV000555969 likely benign not provided 2019-01-28 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 RCV000586026 SCV000696104 likely benign not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1284T>C (p.Asp428Asp) 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 may disrupt and/or create 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 at a frequency of 0.0000165 (2/121396 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). In the literature, the variant was reported in one epithelial ovarian cancer patient without strong evidence for pathogenicity (Pal_BJC_2012). To our knowledge, studies assessing the functional impact of the variant had not been performed at the time of scoring. The variant was observed in an internal sample to co-occur with a pathogenic MLH1 variant c.1772_1775delATAG (p.D591fs*24), suggesting the variant is benign. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is 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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