ClinVar Genomic variation as it relates to human health

Has no predicted effect on splicing and the nucleotide is not conserved across species; Published functional studies are inconclusive: when studied with c.-28A>G, not associated with MLH1 promoter methylation and conflicting results regarding impact on MLH1 expression (Hesson 2015, Morak 2018); Observed with c.-28A>G and in isolation in individuals with MLH1-associated and other cancers (Fredriksson 2006, Hesson 2015, Lagerstedt-Robinson 2016, Morak 2018, Jarhelle 2019, Nikitin 2020); This variant is associated with the following publications: (PMID: 26888055, 25762362, 24689082, 32547938, 16963262, 27601186, 29472279, 31882575)

The c.-7C>T variant in MLH1 is classified as benign because it has been identified in 0.80% (202/25118, 2 homozygotes) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Identified in 2 families with this variant and suggested a partial loss of MLH1 expression (Hesson 2015 PMID:25762362). ACMG/AMP Criteria applied: BA1.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Variant summary: MLH1 c.-7C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0013 in 251462 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.8- fold the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Hereditary Non-Polyposis Colon Cancer phenotype (0.00071), strongly suggesting that the variant is benign. c.-7C>T has been reported in the literature in individuals affected with Hereditary Non-Polyposis Colon Cancer (examples-Hesson_2015, Lagerstedt-Robinson_2016). The variant has also been detected in individuals reported to have hereditary prostate cancer (Fredriksson_2006) and non-HNPCC cancer phenotypes (Morak_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. One publication reports experimental evidence suggesting that the variant results in a 50% reduction in MLH1 expression,however, does not allow convincing conclusions about the variant effect (Hesson_2015). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They cited the variant as benign (n=2) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign.

BS1

The MLH1 c.-7C>T variant was identified in 2 of 980 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Fredriksson 2006, Lagerstedt-Robinson 2016). The variant was also identified in dbSNP (ID: rs104894994) as "With Uncertain significance allele", ClinVar (classified as benign by Invitae; as uncertain significance by GeneDx, InSight and Mayo Clinic), and in LOVD 3.0 (11x). The variant was not identified in UMD-LSDB database. The variant was identified in control databases in 357 of 277232 chromosomes (3 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 13 of 6464 chromosomes (freq: 0.002), Latino in 3 of 34418 chromosomes (freq: 0.00009), European in 132 of 126720 chromosomes (freq: 0.001), Finnish in 207 of 25788 chromosomes (freq: 0.008), and South Asian in 2 of 30782 chromosomes (freq: 0.00007), but not in the African, Ashkenazi Jewish, or East Asian populations. One study by identified that the c.-7C>T variant was associated with partial constitutional loss of MLH1 expression and suggests it is the most likely cause of predisposition to CRC with MMR deficiency and loss of MLH1 (Hesson 2015). However, the same study confirmed the variant co-segregated on the same chromosome with MLH1 c.1164del (predicted to cause a frameshift) in one of the tested probands, increasing the likelihood that the variant does not have clinical significance (Hesson 2015). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Variant interpreted as Uncertain significance and reported on 09-02-2020 by Lab or GTR ID 506138. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.