ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2038T>G (rs63750809)

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Total submissions: 6
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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 colorectal neoplasms 2020-02-13 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 observed in individual(s) with clinical features of Lynch syndrome (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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). This variant disrupts the p.Cys680 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18931482, 25077178, 27601186, 25077178, 23729658). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Health, Inc RCV000579550 SCV000684792 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-17 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000411388 SCV001135006 likely pathogenic Lynch syndrome II 2019-12-07 criteria provided, single submitter clinical testing A Heterozygous missense variation in exon 18 of the MLH1 gene that results in the amino acid substitution of Glycine for Cysteine at codon 680 was detected. The observed variant c.2038T>G (p.Cys680Gly) has previously been reported in the patient affected with colorectal cancer and it is documented as likely pathogenic in InSiGHT and ClinVar database. The p.Cys680Gly variant has not been reported in the 1000 Genomes and has a minor allele frequency of 0.01% in the ExAC databases. The in silico predictions of the variant are damaging by SIFT, LRT and MutationTaster2 tools. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as likely pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000411388 SCV001307913 uncertain significance Lynch syndrome II 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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