ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.306+4A>G (rs267607733)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075633 SCV000106635 uncertain significance Lynch syndrome 2018-10-18 reviewed by expert panel curation Insufficient evidence: splicing not tested in patient RNA
Ambry Genetics RCV000130593 SCV000185466 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000524290 SCV000543612 uncertain significance Hereditary nonpolyposis colon cancer 2018-05-07 criteria provided, single submitter clinical testing This sequence change falls in intron 3 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 present in population databases (rs267607733, ExAC 0.005%). This variant has been reported in individuals affected with Lynch syndrome (PMID: 18561205) and breast and/or ovarian cancer (PMID: 26898890). ClinVar contains an entry for this variant (Variation ID: 90147). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change results in the activation of a cryptic donor site and the skipping of exon 3 in an ex vivo splicing minigene assay (PMID: 18561205). 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.
GeneDx RCV000482840 SCV000565142 uncertain significance not provided 2018-03-19 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.306+4A>G or IVS3+4A>G and consists of an A>G nucleotide substitution at the +4 position of intron 3 of the MLH1 gene. In-silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. This variant was identified in at least one individual with personal and/or family history suggestive of Lynch syndrome and was reported to cause skipping of exon 3 in an ex vivo splicing assay; however patient RNA was not studied to confirm these findings (Tournier 2008). This variant was also observed in an individual with a personal history of breast cancer and a family history of breast and ovarian cancer (Caminsky 2016). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as being of uncertain significance (Thompson 2014). MLH1 c.306+4A>G 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.306+4A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130593 SCV000684817 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
GeneKor MSA RCV000130593 SCV000822023 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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