ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.-27C>A (rs587779001)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132376 SCV000187467 pathogenic Hereditary cancer-predisposing syndrome 2018-03-05 criteria provided, single submitter clinical testing <u><span style="background-color:#FF0000">****************<span style="background-color:#FF0000">HAPTOTYPE<span style="background-color:#FF0000"> RD************************</u> The c.-27C>A alteration is located in the 5' untranslated region (5&rsquo;UTR) of the MLH1 gene. This variant results from a C to A substitution 27 nucleotides upstream from the first translated codon. The p.A29S alteration (also known as c.85G>T) is located in coding exon 1 of the MLH1 gene. This alteration results from a G to T substitution at nucleotide position 85. The alanine at codon 29 is replaced by serine, an amino acid with similar properties. The c.-27C>A and p.A29S alterations are linked in cis, as both are part of a European ancestral haplotype. Three reportedly unrelated HNPCC/Lynch syndrome families have been described in which the c.-27C>A + p.A29S haplotype segregated with a mosaic MLH1 epimutation (Kwok CT et al, Eur. J. Hum. Genet. 2014 May;22(5):617-24.). Within these families, the c.-27C>A + p.A29S haplotype was associated with loss of MLH1 and PMS2 staining in tumor samples and inconsistent levels of MLH1 promoter methylation/transcriptional silencing in normal tissues. Combined with results from two additional HNPCC/Lynch syndrome families, this data strongly supports the association between the c.-27C>A + p.A29S haplotype and a high-risk, inherited MLH1 epimutation (Hitchins MP et al. Cancer Cell 2011;20:200-13; Ward RL et al. Genet. Med. 2013;15:25-35). Luciferase reporter assays performed by Hitchins and colleagues suggest that the c.-27C>A alteration, and not p.A29S, accounts for repression of MLH1 transcription; however, a direct causal relationship has yet to be clarified. Based on the available evidence, the c.-27C>A + p.A29S haplotype is classified as pathogenic. <span style="background-color:#FF0000">************************c.-27C>A alone RD**************************(use only when p.A29S is not identified with c.-27C>A)***************<br /> The c.-27C>A alteration is located in the 5' untranslated region (5&rsquo;UTR) of the MLH1 gene. This variant results from a C to A substitution 27 nucleotides upstream from the first translated codon. This alteration has been reported in multiple unrelated HNPCC/Lynch syndrome families as part of a haplotype in conjunction with MLH1 p.A29S (Kwok CT et al, Eur. J. Hum. Genet. 2014 May;22(5):617-24; Hitchins MP et al. Cancer Cell 2011;20:200-13; Ward RL et al. Genet. Med. 2013;15:25-35). Within these families, the c.-27C>A + p.A29S haplotype was associated with loss of MLH1 and PMS2 staining in tumor samples and inconsistent levels of MLH1 promoter methylation/transcriptional silencing in normal tissues. However, luciferase reporter assays performed by Hitchins and colleagues suggest that the c.-27C>A alteration, and not p.A29S, reduced MLH1 promoter activity significantly and that retention of cytosine at position -27 is crucial for optimal MLH1 transcription in somatic cells. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx RCV000214578 SCV000279472 pathogenic not provided 2018-11-27 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.-27C>A and describes a nucleotide substitution 27 base pairs upstream of the ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence, with the base that is substituted in brackets, is TAGA[C/A]GTTT. MLH1 c.-27C>A has been consistently reported to be located in cis with MLH1 c.85G>T (p.Ala29Ser) as a haplotype and has been observed in at least five families with Lynch syndrome associated cancers (Raevaara 2005, Hitchins 2011, Ward 2013, Kwok 2014). This haplotype co-segregated with colorectal cancer in at least three families and tumor analyses of respective cancers exhibited microsatellite instability and abnormal MLH1 staining on immunohistochemistry (Raevaara, 2005, Hitchins 2011, Ward 2013, Kwok 2014). Although this variant does not appear to affect the start codon or the Kozak translational consensus sequence, functional studies show this haplotype to be associated with constitutional MLH1 promoter methylation and reduced allelic expression (Hitchins 2011, Kwok 2014). Furthermore, in vitro analyses of MLH1 c.-27C>A in isolation showed significantly reduced promoter activity (Hitchins 2011). MLH1 c.-27C>A occurs at a position that is not conserved. MLH1 c.-27C>A was not observed in large population cohorts (Lek 2016). Based on the current evidence, we consider this variant to be pathogenic.
Counsyl RCV000662782 SCV000785591 likely pathogenic Lynch syndrome II 2017-09-26 criteria provided, single submitter clinical testing
Invitae RCV000695005 SCV000823479 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-18 criteria provided, single submitter clinical testing This sequence change falls in the promoter region of the MLH1 gene. It does not change the encoded amino acid sequence of the MLH1 protein, but occurs in a region important for transcription of the MLH1 gene. This variant is not present in population databases (ExAC no frequency). This variant has been reported on the same chromosome with the c.85G>T (p.Ala29Ser) missense MLH1 variant in numerous individuals affected with Lynch syndrome (PMID: 21840485, 16083711, 22878509), and was reported to segregate with disease in several families (PMID: 24084575, 21840485). ClinVar contains an entry for this variant (Variation ID: 89589). Experimental studies have shown that the combined c.-27C>A and c.85G>T haplotype is associated with constitutional MLH1 promoter methylation, which reduces the promoter activity. Moreover, the c.-27C>A alone diminishes promoter activity to a similar extent as the combined haplotype (PMID: 21840485, 22878509). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000583780 SCV000691839 uncertain significance not specified no assertion criteria provided clinical testing

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