ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.601G>C (p.Val201Leu) (rs534184145)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165537 SCV000216269 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000221109 SCV000279077 uncertain significance not provided 2018-05-29 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.601G>C at the cDNA level, p.Val201Leu (V201L) at the protein level, and results in the change of a Valine to a Leucine (GTA>CTA). This variant was observed in at least one individual with pancreatic cancer (Grant 2015). MLH1 Val201Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether MLH1 Val201Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000472998 SCV000543601 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 201 of the MLH1 protein (p.Val201Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with pancreatic cancer (PMID: 25479140). ClinVar contains an entry for this variant (Variation ID: 186017). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Counsyl RCV000663069 SCV000786136 uncertain significance Lynch syndrome II 2018-03-06 criteria provided, single submitter clinical testing
Color RCV000165537 SCV000911476 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing

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