ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1667G>C (p.Ser556Thr) (rs63751596)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164556 SCV000215214 likely pathogenic Hereditary cancer-predisposing syndrome 2014-06-26 criteria provided, single submitter clinical testing Last nucleotide of exon;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000164556 SCV000905471 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-18 criteria provided, single submitter clinical testing
Invitae RCV000822496 SCV000963303 likely pathogenic Hereditary nonpolyposis colon cancer 2019-12-01 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 556 of the MLH1 protein (p.Ser556Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant also falls at the last nucleotide of exon 14 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs63751596, ExAC 0.001%). This variant has been observed in individuals with suspected Lynch syndrome (PMID: 28514183). ClinVar contains an entry for this variant (Variation ID: 185187). 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 C55"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide (c.1667G>A) has been determined to be pathogenic (PMID: 28135145, 27064304, Invitae, external communication). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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.
Integrated Genetics/Laboratory Corporation of America RCV001193962 SCV001363158 uncertain significance not specified 2019-03-07 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1667G>C (p.Ser556Thr) results in a conservative amino acid change located in the DNA mismatch repair protein MLH1, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Additionally, c.1667G>C alters a conserved nucleotide located within the confines of a putative splice region at the end of exon 14. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' donor site. One predict the variant abolishes the canonical 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. Nevertheless, a variant located at the same nucleotide position but causing a different change (MLH1 c.1667G>T) is predicted by computational tools to cause a very similar effect on splicing as the variant of interest. c.1667G>T (not the variant of interest) was reported to cause the inclusion of an additional 88bp of intronic sequence into the mRNA resulting in a frameshift and the inclusion of a stop codon in the additional intronic sequence (Sharp_2004). Therefore, the possibility of this variant (c.1667G>C) having a similar splicing outcome cannot be ruled out. The variant allele was found at a frequency of 4.1e-06 in 245968 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1667G>C has been reported in the literature in individuals affected with features of Lynch syndrome whose tumors were MSI-high and showed positive staining for MLH1 by IHC (Alter_2018, Hardt_2011). Specifically, a non-peer reviewed case report of co-occurrence with a putative pathogenic variant in MSH2 gene was ascertained at the time of this classification (MSH2 deletion of exon 9) (Alter_2018). This index patient had a MSI-high mucinous carcinoma in the colon ascendens at the age of 38. Immunohistochemical staining showed a loss of MSH2 and MSH6 expression. 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. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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