ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1153C>T (p.Arg385Cys) (rs63750760)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524225 SCV000262140 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 385 of the MLH1 protein (p.Arg385Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs63750760, ExAC 0.03%). This variant has been reported to segregate with colon cancer in one family (PMID: 11839723, 15222003) and has been found in unrelated individuals with colon cancer (PMID: 10348818). This variant has also been observed in an individual with pancreatic ductal adenocarcinoma (PMID: 27732944) as well as in individuals with a personal and/or family history of breast or ovarian cancer (PMID: 24549055, 26845104). ClinVar contains an entry for this variant (Variation ID: 89653). 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. 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000075124 SCV000266073 uncertain significance Lynch syndrome 2017-07-11 criteria provided, single submitter clinical testing
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490290 SCV000267395 uncertain significance Lynch syndrome II 2016-03-18 criteria provided, single submitter reference population
Ambry Genetics RCV000217569 SCV000273951 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
GeneDx RCV000656862 SCV000565154 uncertain significance not provided 2018-04-03 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1153C>T at the cDNA level, p.Arg385Cys (R385C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been observed in at least one family with colorectal cancer, in which the variant was reported to co-segregate with disease; however, it is unclear which individuals in this family had genetic testing (Cravo 2002), as well as in an individual with a clinical diagnosis of Familial Adenomatous Polyposis who also harbored a pathogenic variant in APC (Shang 2018). This variant has also been observed in at least one individual with a personal and/or family history of breast and/or ovarian cancer, and in one individual with early onset breast cancer (Castera 2014, Wong 2016), but was also observed in one unaffected individual in a population-based whole exome sequencing study (Natarajan 2016). MLH1 Arg385Cys was observed at an allele frequency of 0.046% (8/17248) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Arg385Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000217569 SCV000684720 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000202088 SCV000711742 uncertain significance not specified 2016-06-16 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg385Cys variant in MLH1 has been reported in at least 2 individuals with MLH1-associate d cancers and segregated with disease in multiple relatives from 1 family (Cravo 2002, Lage 2004, Chao 2008, Shirts 2016). This variant has also been identified in 3/8648 of East Asian chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs63750760). This frequency is low enough to be consistent with the frequency of Lynch syndrome in the general population. Computational prediction tools and conservation analysis suggest that the p.Arg 385Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion fo r a pathogenic role, the clinical significance of the p.Arg385Cys variant is unc ertain.
Fulgent Genetics,Fulgent Genetics RCV000764489 SCV000895560 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000202088 SCV000919636 uncertain significance not specified 2018-02-07 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1153C>T (p.Arg385Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 246288 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (5.3e-05 vs 7.10E-04), allowing no conclusion about variant significance. The c.1153C>T variant has been reported in the literature in multiple individuals affected with Lynch Syndrome, as well as breast cancer and other cancers, without strong evidence for or against pathogenicity. Thus, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; five laboratories classified the variant as uncertain significance, while one laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202088 SCV000257044 uncertain significance not specified no assertion criteria provided research

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