ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.-42C>T

gnomAD frequency: 0.00009  dbSNP: rs41285097
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Total submissions: 10
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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.
GeneDx 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, part of Exact Sciences RCV000679261 SCV000805937 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized 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, 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, Sinai Health System 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.

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