ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.194G>A (p.Gly65Asp) (rs63751465)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075435 SCV000106431 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
Invitae RCV001201396 SCV000543660 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 65 of the MLH1 protein (p.Gly65Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with colorectal cancer (PMID: 14514376, 18094436), and an individual affected with breast cancer (PMID: 25927356) This variant has been reported to affect MLH1 protein function (PMID: 23403630, 18094436, 15475387). Based on a multifactorial likelihood algorithm using genetic, clinical, in silico and functional data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000564174 SCV000676062 likely pathogenic Hereditary cancer-predisposing syndrome 2019-07-31 criteria provided, single submitter clinical testing The p.G65D variant (also known as c.194G>A), located in coding exon 2 of the MLH1 gene, results from a G to A substitution at nucleotide position 194. The glycine at codon 65 is replaced by aspartic acid, an amino acid with similar properties. This variant was identified in a Chinese woman with MSI-high colorectal cancer demonstrating loss of MLH1 protein by immunohistochemistry, and it was identified in 0/112 controls (Fan Y et al. Clin. Cancer Res. 2007 Dec;13:7515-21). This alteration has also been reported in a Chinese patient with breast cancer diagnosed at age 52 who also met revised Bethesda criteria for Lynch syndrome (Yang X et al. PLoS ONE 2015 Apr;10:e0125571). In addition, functional analyses have demonstrated at least partial loss of mismatch repair activity associated with this alteration, which is found in the ATP-binding domain (Ellison AR et al. Nucleic Acids Res. 2004 Oct;32:5321-38; Fan Y et al. Clin. Cancer Res. 2007 Dec;13:7515-21; Hinrichsen I et al. Clin. Cancer Res. 2013 May;19:2432-41). This alteration has been classified as likely pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at []). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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