ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1936T>C (p.Tyr646His)

dbSNP: rs1553663884
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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 RCV001013771 SCV001174398 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-30 criteria provided, single submitter clinical testing The p.Y646H variant (also known as c.1936T>C), located in coding exon 17 of the MLH1 gene, results from a T to C substitution at nucleotide position 1936. The tyrosine at codon 646 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001363842 SCV001559971 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-01-29 criteria provided, single submitter clinical testing 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. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MLH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 646 of the MLH1 protein (p.Tyr646His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001824913 SCV002074399 uncertain significance not specified 2022-01-22 criteria provided, single submitter clinical testing

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