ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1667G>C (p.Ser556Thr) (rs63751596)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164556 SCV000215214 likely pathogenic Hereditary cancer-predisposing syndrome 2017-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000164556 SCV000905471 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-16 criteria provided, single submitter clinical testing
Invitae RCV000822496 SCV000963303 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 556 of the MLH1 protein (p.Ser556Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant also falls at the last nucleotide of exon 14 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs63751596, ExAC 0.001%). This variant has been observed in individuals with suspected Lynch syndrome (PMID: 28514183). ClinVar contains an entry for this variant (Variation ID: 185187). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, 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.

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