ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1154G>A (p.Arg385His) (rs63750430)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128876 SCV000172733 likely benign Hereditary cancer-predisposing syndrome 2020-09-11 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
Invitae RCV000232561 SCV000284007 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 385 of the MLH1 protein (p.Arg385His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs63750430, ExAC 0.02%). This variant has been reported in individuals in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 140759). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000409286 SCV000488610 uncertain significance Lynch syndrome II 2016-05-10 criteria provided, single submitter clinical testing
GeneDx RCV000657135 SCV000570352 uncertain significance not provided 2018-11-08 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1154G>A at the cDNA level, p.Arg385His (R385H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MLH1 Arg385His was observed at an allele frequency of 0.02% (6/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Arg385His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657135 SCV000601346 uncertain significance not provided 2020-01-14 criteria provided, single submitter clinical testing
Mendelics RCV000708920 SCV000838010 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764490 SCV000895561 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000128876 SCV000911263 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-04 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 385 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in unaffected individuals in a pancreatic case-control study (PMID: 32980694) and in an individual affected with Ewing sarcoma (PMID: 27498913). This variant has been identified in 15/282582 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000484459 SCV000919660 uncertain significance not specified 2018-08-31 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1154G>A (p.Arg385His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 276920 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (5.4e-05 vs 7.10e-04), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1154G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000409286 SCV001136401 uncertain significance Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000409286 SCV001307794 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.
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249936 SCV001423878 uncertain significance Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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