ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1269G>A (p.Arg423=) (rs373076967)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212534 SCV000211141 benign not specified 2014-07-16 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.
Ambry Genetics RCV000160562 SCV000213054 likely benign Hereditary cancer-predisposing syndrome 2014-11-25 criteria provided, single submitter clinical testing
Invitae RCV001086876 SCV000259880 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000662830 SCV000443335 uncertain significance Lynch syndrome II 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212534 SCV000601349 likely benign not specified 2016-12-08 criteria provided, single submitter clinical testing
Color RCV000160562 SCV000684735 likely benign Hereditary cancer-predisposing syndrome 2016-07-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589453 SCV000696103 likely benign not provided 2017-06-23 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1269G>A (p.Arg423Arg) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change that 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE binding sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 8/121400 control chromosomes at a frequency of 0.0000659, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). A publication cites the variant in 2 pts diagnosed with ovarian cancer, however, limited information is provided (ie, no co-occurrence or cosegregation data). An internal LCA sample reports the variant to co-olccur with two MUTYH DVs, c.536A>G and c.1187G>A. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as "likely benign."
Counsyl RCV000662830 SCV000785682 likely benign Lynch syndrome II 2017-10-31 criteria provided, single submitter clinical testing

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