ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.545+3A>G (rs267607760)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075749 SCV000106757 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration, >2 MSI-H, co-segregation with disease & absent in 1000 genomes
GeneDx RCV000215515 SCV000279598 pathogenic not provided 2017-11-10 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.545+3A>G or IVS6+3A>G and consists of an A>G nucleotide substitution at the +3 position of intron 6 of the MLH1 gene. In-silico analyses, including splice predictors and evolutionary conservation, support a deleterious effect. RNA studies and protein truncation testing confirm this prediction, demonstrating abnormal splicing leading to a frameshift that results in a truncated protein (Pensotti 1997, Thiffault 2004). This variant was observed in multiple individuals with colon cancer, including two who had absent MLH1 on immunohistochemistry, and is considered an Italian pathogenic founder variant (Pensotti 1997, Hendriks 2003, Liu 2004, Thiffault 2004, Mangold 2005, Valentin 2011). This variant has been shown to segregate with disease in two affected siblings in one family and with three affected relatives in another family (Thiffault 2004). MLH1 c.545+3A>G was not observed in large population cohorts (Lek 2016). The adenine (A) nucleotide that is altered is conserved across species. Based on the current evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000564669 SCV000676016 pathogenic Hereditary cancer-predisposing syndrome 2017-07-27 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Integrated Genetics/Laboratory Corporation of America RCV000075749 SCV000696170 pathogenic Lynch syndrome 2016-09-19 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.545+3A>G variant involves the alteration of a conserved nucleotide located at the intron/exon boundary. One in silico tool predicts a damaging outcome for this variant. 4/4 splice prediction tools predict loss/weakening effect on the canonical splicing donor site. This variant was absent in 121426 control chromosomes but has been reported in multiple affected individuals/families, and some families showed evidence of co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. RT-PCR showed the variant lead to an aberrant splicing product (Pensotti_GCC_1997). Taken together, this variant was classified as pathogenic.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000075749 SCV000914314 pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
Color RCV000564669 SCV001340977 pathogenic Hereditary cancer-predisposing syndrome 2018-11-27 criteria provided, single submitter clinical testing
Invitae RCV001202202 SCV001373307 pathogenic Hereditary nonpolyposis colon cancer 2019-09-26 criteria provided, single submitter clinical testing This sequence change falls in intron 6 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with clinical features of Lynch syndrome and has also been observed in individuals with Lynch syndrome (PMID: 15253764, 9218993, 12547705, 28874130, 26437257, 15849733, 15309712). This variant is also known as IVS6+3A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 90260). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 9218993, 15253764). For these reasons, this variant has been classified as Pathogenic.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000609647 SCV000734263 pathogenic Lynch syndrome II no assertion criteria provided clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249949 SCV001423891 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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