Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000131249 | SCV000186211 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-01-03 | criteria provided, single submitter | clinical testing | The c.-42C>T variant is located in the 5' untranslated region (5’ UTR) of the MLH1 gene. This variant results from a C to T substitution 42 nucleotides upstream from the first translated codon. This alteration has been reported in multiple suspected-HNPCC/Lynch syndrome patients to date; however microsatellite instability (MSI) and immunohistochemistry (IHC) results from these individuals have been inconsistent (Müller-Koch Y et al. Eur. J. Med. Res. 2001; 6:473-82, Green RC et al. Clin. Genet. 2003; 64:220-7, Mangold E et al. Int. J. Cancer 2005; 116:692-702, Ward RL et al. Genet. Med. 2013; 15:25-35). Artificial promoter reporter assays have shown a c.-42C>T-associated reduction in activity between 37-80% of wild type levels (Green RC et al. Clin. Genet. 2003; 64:220-7, Ward RL et al. Genet. Med. 2013; 15:25-35). This nucleotide position is well conserved in available vertebrate species. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear. |
Gene |
RCV000679261 | SCV000211123 | uncertain significance | not provided | 2023-04-17 | criteria provided, single submitter | clinical testing | Describes a nucleotide substitution 42 base pairs upstream of the ATG translational start site; Published functional studies are conflicting: demonstrates reduced promoter activity in experimental cell lines while cDNA analysis from one carrier showed MLH1 expression was not impacted (Green et al., 2003; Ward et al., 2013; Morak et al., 2018); Observed in individuals with suspected Lynch syndrome, some with colon tumors showing loss of MLH1 expression by immunohistochemistry (IHC) (Green et al., 2003; Mangold et al., 2005; Ward et al., 2013; Yurgelun et al., 2015; Morak et al., 2018); Has no predicted effect on splicing and the nucleotide is not conserved; This variant is associated with the following publications: (PMID: 11726306, 15849733, 22878509, 12919137, 26332594, 25980754, 25762362, 26888055, 23462881, 28640387, 29472279, 29490919, 32719484, 17895478) |
Invitae | RCV000524298 | SCV000283993 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2020-07-16 | criteria provided, single submitter | clinical testing | This variant occurs in a non-coding region of the MLH1 gene. It does not change the encoded amino acid sequence of the MLH1 protein. This variant is present in population databases (rs41285097, ExAC 0.005%). This variant has been observed in individual(s) with clinical features of autosomal dominant Lynch syndrome (PMID: 12919137, 11726306, 29472279, 22878509). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89593). This variant has been reported to have conflicting or insufficient data to determine the effect on MLH1 protein function (PMID: 12919137, 22878509). 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. |
Counsyl | RCV000410786 | SCV000488806 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2016-06-21 | criteria provided, single submitter | clinical testing | |
Preventiongenetics, |
RCV000679261 | SCV000805937 | uncertain significance | not provided | 2017-07-06 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000825373 | SCV000966668 | uncertain significance | not specified | 2018-09-18 | criteria provided, single submitter | clinical testing | The c.-42C>T variant in MLH1 has been reported in 5 individuals with colorectal cancer (Green 2003, Mangold 2005, Ward 2013, Yurgelun 2015, Morak 2018), and seg regated with disease in two individuals from 1 family (Green 2003). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 8959 3) and has also been identified in 0.01% (12/126682) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). The c.-42C>T variant is located in th e 5' UTR, but its effect on translation is unknown. In vitro functional studies provide some evidence that it may impact protein function (Green 2003, Ward 2013 ). In summary, the clinical significance of the c.-42C>T variant is uncertain. A CMG/AMP Criteria applied: PS3_Supporting, PS4_Supporting. |
Fulgent Genetics, |
RCV002477215 | SCV002775936 | uncertain significance | Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2 | 2021-07-27 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000410786 | SCV004195087 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-09-30 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000410786 | SCV000038908 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2003-09-01 | no assertion criteria provided | literature only | |
Department of Pathology and Laboratory Medicine, |
RCV000075062 | SCV000592324 | uncertain significance | Familial colorectal cancer | no assertion criteria provided | clinical testing | The MLH1 c.-42C>T variant was identified in 5 of 7756 proband chromosomes (frequency: 0.0006) from individuals or families with colorectal cancer (Morak 2018, Green 2003, Yurgelun 2015, Ward 2013, Mangold 2005). The variant was identified in dbSNP (rs41285097) as 'Auwith uncertain significance allele' and ClinVar (classified as uncertain significance by Invitae, Counsyl, Ambry Genetics, PreventionGenetics, GeneDx, Partners Healthcare and OMIM). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 14 of 268,324 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 13 of 118,166 chromosomes (freq: 0.0001) and African in 1 of 23,618 chromosomes (freq: 0.00004); it was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The variant was identified in two affected members of a family with colorectal cancer, one of whom had an MLH1-deficient tumour (Green 2003). In addition, the variant was demonstrated to significantly reduce, but not abolish, MLH1 transcriptional activity; however, the effect on translation is not known (Green 2003, Ward 2013). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |