ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.27G>A (p.Arg9=) (rs759680369)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166655 SCV000217460 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-22 criteria provided, single submitter clinical testing The c.27G>A variant (also known as p.R9R), located in coding exon 1 of the MLH1 gene, results from a G to A substitution at nucleotide position 27. This nucleotide substitution does not change the amino acid at codon 9. This alteration was detected along with low-level constitutional MLH1 promoter methylation in a Caucasian male with 3 colorectal cancers, one of which demonstrated high microsatellite instability (MSI-H) with loss of MLH1 protein expression on immunohistochemistry (IHC). The father and mother of this proband were both diagnosed with colorectal cancer as well as a son, who died at age 22 from colorectal cancer. The son also carried the c.27G>A variant allele along with low-level constitutional​ MLH1 promoter methylation; however, two affected maternal family members did not carry this alteration and were negative for constitutional​ MLH1 promoter methylation indicating the variant allele may have been paternally inherited (Ward RL et al. Genet. Med. 2013 Jan;15:25-35). This alteration was also reported in a French family that fulfilled Amsterdam I criteria and exhibited low-level constitutional​ MLH1 promoter methylation. Four family members, two diagnosed with colorectal cancer and two with colorectal adenomas, carried the c.27G>A allele along with low-level constitutional MLH1 promoter methylation. This alteration was identified in another unrelated individual in this study who was diagnosed with colorectal cancer as well as endometrial cancer and had constitutional​ MLH1 promoter methylation (Leclerc J et al. Genet. Med. 2018 12;20:1589-1599). In our clinical cohort, this alteration also segregated with low-level constitutional MLH1 promoter methylation and disease in families meeting clinical diagnostic criteria for Lynch syndrome (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice donor site. RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000471119 SCV000555984 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change affects codon 9 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with Lynch syndrome, and shown to segregate in families with Lynch syndrome-associated tumors (PMID: 29790873, 22878509, Invitae). ClinVar contains an entry for this variant (Variation ID: 186982). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.

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