ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2038T>G (p.Cys680Gly) (rs63750809)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411388 SCV000488878 uncertain significance Lynch syndrome II 2016-07-12 criteria provided, single submitter clinical testing
Invitae RCV000684822 SCV000543523 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 680 of the MLH1 protein (p.Cys680Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is present in population databases (rs63750809, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with colon, rectal, breast, ureter, and skin cancer (PMID: 15345113). ClinVar contains an entry for this variant (Variation ID: 90007). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 RCV000483931 SCV000567226 uncertain significance not provided 2016-04-12 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2038T>G at the cDNA level, p.Cys680Gly (C680G) at the protein level, and results in the change of a Cysteine to a Glycine (TGC>GGC). This variant has been reported in a woman with a personal history of four separate malignancies including breast, rectal, colon and ureter (Rajkumar 2004). MLH1 Cys680Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Cys680Gly occurs at a position that is conserved in mammals and is located in the region of interaction with PMS2, MLH3 and PMS1 (Raevaara 2005). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Cys680Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000579550 SCV000684792 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing

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