ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.453G>A (p.Thr151=) (rs369521379)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000680177 SCV000106723 uncertain significance Lynch syndrome I 2018-06-13 reviewed by expert panel curation Criteria changed for variants in last base of exon therefore downgrade classification
Ambry Genetics RCV000132472 SCV000187566 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
University of Washington Department of Laboratory Medicine,University of Washington RCV000075718 SCV000266182 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.453G>A has a 75.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214. This was also reported in Shirts et al 2016, PMID 26845104 in an individual with a family history of colorectal cancer.
GeneDx RCV000590027 SCV000279445 uncertain significance not provided 2019-01-02 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.453G>A at the DNA level. It is silent at the coding level, preserving a Threonine at codon 151. Located in the last nucleotide of exon 5, this variant may damage the nearby splice donor site and cause abnormal splicing. In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has been identified in at least two individuals with a personal history of colon cancer and/or polyps (Shirts 2016, Sunga 2017). MLH1 c.453G>A was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether MLH1 c.453G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000524300 SCV000284064 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change affects codon 151 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. It also falls at the last nucleotide of exon 5 of the MLH1 coding sequence. This variant is present in population databases (rs369521379, ExAC 0.006%). This variant has been observed in individuals with colon cancer (PMID: 26845104, 28449805). ClinVar contains an entry for this variant (Variation ID: 90229). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.
Integrated Genetics/Laboratory Corporation of America RCV000221643 SCV000696166 uncertain significance not specified 2019-01-02 criteria provided, single submitter clinical testing Variant summary: The variant, MLH1 c.453G>A (p.Thr151Thr) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant alters the last nucleotide of exon 5 and several computational tools predict that this variant may affect splicing as it weakens the canonical splice donor site and creates an acceptor site . However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.1e-05 in 277158 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (1.1e-05 vs 0.00071), allowing no conclusion about variant significance. The variant, c.453G>A has been reported in the literature in individuals affected with Lynch syndrome (Sunga_2017). These reports however do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. The variant of interest has also been reported in at least one cancer-free individual with the personal history of polyps and family history of CRC (Shirts_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.188T>A, p.Leu63X). Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) have cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000590027 SCV000702752 uncertain significance not provided 2016-10-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000221643 SCV000712856 uncertain significance not specified 2017-02-21 criteria provided, single submitter clinical testing The p.Thr151Thr variant in MLH1 has been reported in one individual with colorec tal polyps and a family history of colorectal cancer (Shirts 2016). This variant has been identified in 1/16492 of South Asian chromosomes by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs369521379). Althou gh the p.Thr151Thr variant does not alter an amino acid residue, it is located i n the last base of the exon, which is part of the 5? splice region. Computationa l tools suggest some impact to splicing though this information is not predictiv e enough to determine pathogenicity. In contrast, this variant has been classifi ed as Likely Pathogenic on Sept 5, 2013 by the ClinGen-approved InSiGHT expert p anel (ClinVarSCV000106723.2), due a predicted splicing effect that has not been confirmed by published functional studies. In summary, the clinical significance of the p.Thr151Thr variant is uncertain.
Color RCV000132472 SCV000903439 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590027 SCV001134313 uncertain significance not provided 2019-03-07 criteria provided, single submitter clinical testing
Mendelics RCV000987151 SCV001136377 likely pathogenic Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing

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