ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1572G>C (p.Met524Ile) (rs587779953)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115462 SCV000149371 uncertain significance not provided 2013-10-08 criteria provided, single submitter clinical testing This variant in exon 14 of the MLH1 gene is denoted c.1572G>C at the cDNA level and p.Met524Ile (M524I) at the protein level. The M524I variant has not been published as a mutation nor has it been reported as a benign polymorphism, to our knowledge. The NHLBI ESP Exome Variant Server reports M524I was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. This amino acid substitution results in the conservative replacement of a neutral, non-polar Methionine residue (ATG) with a neutral, non-polar Isoleucine residue (ATC) at a position that is conserved throughout evolution. The M524I variant is located in a domain of MLH1 that interacts with exonuclease 1; and multiple in silico algorithms predict that this variant may be benign. Previously reported mutations in nearby codons are predominantly nonsense changes. Based on the currently available information, it is unclear whether M524I is a pathogenic mutation or a rare benign variant.The variant is found in BR-OV-HEREDIC panel(s).
Ambry Genetics RCV001012209 SCV001172635 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030629 SCV001193611 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Invitae RCV001058475 SCV001223049 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 524 of the MLH1 protein (p.Met524Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 127616). 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 tolerated, 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.
Illumina Clinical Services Laboratory,Illumina RCV001149457 SCV001310409 uncertain significance Lynch syndrome II 2018-01-13 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.
Color RCV001012209 SCV001351186 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192573 SCV001360800 uncertain significance not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1572G>C (p.Met524Ile) results in a conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251158 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1572G>C has been reported in the literature as somatic occurrences (Kobayashi_2019 and Sakai_2015). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (APC c.3184_3187delCAAA, p.Gln1062ValfsX63). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

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