ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2103G>C (p.Gln701His) (rs63750603)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075534 SCV000106531 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causing splicing aberration predicted to interrupt known functional domains: full inactivation of variant allele
Integrated Genetics/Laboratory Corporation of America RCV000075534 SCV000696146 pathogenic Lynch syndrome 2017-04-20 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.2103G>C (p.Gln701His) variant involves the alteration of a conserved nucleotide at the last coding position at the exon 18-intron 18 junction, which lies within the DNA mismatch repair protein MLH1, C-terminal domain (InterPro). 3/5 in silico tools predict a benign outcome for this variant. However, 4/5 splice prediction tools predict a significant impact on normal splicing and functional assays do indeed suggest aberrant splicing due to the variant. In one study, RNA analysis in the blood sample of a patient carrying the variant showed an abnormal transcript compared to controls, and sequence analysis revealed exon 18 skipping in this variant transcript (Pagenstecher_2006). This study found the variant in 4 patients with evidence of cosegregation within the families. In a separate publication, the same research group performed immunohistochemistry assays that showed tumor tissue from two members of one of the families (Family 485) was MLH1 deficient (Mangold_2005). This variant is absent in the large control databases ExAC (0/119918 control chromosomes) and gnomAD (0/276412 control chromosomes). In addition, one reputable database has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000694604 SCV000823055 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-02-21 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 701 of the MLH1 protein (p.Gln701His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 18 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Lynch syndrome (PMID: 15849733, 16216036) and has been reported to segregate with Lynch syndrome-related cancers in several families (PMID: 21404177). ClinVar contains an entry for this variant (Variation ID: 90049). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). An experimental study has shown that this missense change results in skipping of exon 18 of MLH1 in mRNA derived from an affected individual (PMID: 16341550). 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 RCV001014446 SCV001175153 pathogenic Hereditary cancer-predisposing syndrome 2019-02-08 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Functionally-validated splicing mutation;Last nucleotide of exon
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093697 SCV001250881 pathogenic Lynch syndrome I no assertion criteria provided clinical testing

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