ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.790C>T (p.His264Tyr) (rs63751597)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478542 SCV000565146 uncertain significance not provided 2017-05-16 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.790C>T at the cDNA level, p.His264Tyr (H264Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). This variant was observed in an individual with early onset colorectal cancer in which tumor studies revealed microsatellite instability and absent MLH1 immunohistochemical staining, however, this individual and his affected mother also harbored a known pathogenic MLH1 variant in cis (Chan 1999, Yuen 2002). MLH1 His264Tyr was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 His264Tyr occurs at a position that is conserved across species and is located in the N-terminal ATPase domain (Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 His264Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000530665 SCV000625195 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-09-16 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 264 of the MLH1 protein (p.His264Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs63751597, ExAC 0.006%). This variant has been reported in two individuals from a single family affected with colorectal cancer, who also carried a pathogenic allele in MLH1 on the same chromosome (PMID: 10413423). ClinVar contains an entry for this variant (Variation ID: 90367). 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant falls at the last nucleotide of exon 9 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). However, an experimental study has shown that this missense change does not affect splicing (PMID: 10413423). 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.
Ambry Genetics RCV000562121 SCV000669560 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-23 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000562121 SCV001345268 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193965 SCV001363161 uncertain significance not specified 2019-08-23 criteria provided, single submitter clinical testing Variant summary: MLH1 c.790C>T (p.His264Tyr) results in a conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Despite the variant being located at the last nucleotide position in exon 9, 5/5 computational tools predict no significant impact on normal splicing. Additionally, no truncated protein product was detected in a patient sample carrying the variant, supporting the lack of impact of this variant on splicing (Chan_1999). The variant allele was found at a frequency of 1.6e-05 in 250062 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.790C>T has been reported in the literature in a mother and son with colorectal cancer who also carried another pathogenic variant MLH1 c.350C>T (p.T117M), providing supporting evidence for a benign role (Chan_1999, Yuen_2002). One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Bouvet_2019). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093687 SCV001250870 uncertain significance Lynch syndrome I no assertion criteria provided clinical testing

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