ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1918C>T (p.Pro640Ser) (rs63749792)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075424 SCV000106419 likely pathogenic Lynch syndrome 2018-10-18 reviewed by expert panel curation Abrogated function & >2 MSI-H tumours
Invitae RCV000791363 SCV000254362 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-05-23 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 640 of the MLH1 protein (p.Pro640Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome (PMID: 15365995, 22854115, 24278394, 24292105), and was reported to segregate with disease in two families (PMID: 16276679, Invitae). ClinVar contains an entry for this variant (Variation ID: 89945). This variant has been reported to affect MLH1 protein function (PMID: 21404117, 23403630). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000569430 SCV000676063 pathogenic Hereditary cancer-predisposing syndrome 2019-01-29 criteria provided, single submitter clinical testing The p.P640S variant (also known as c.1918C>T), located in coding exon 17 of the MLH1 gene, results from a C to T substitution at nucleotide position 1918. The proline at codon 640 is replaced by serine, an amino acid with similar properties. This alteration has been reported in multiple individuals with personal and/or family histories suggestive of, or consistent with, Lynch syndrome (Shin YK et al. Hum. Mutat. 2004 Oct;24:351; Giraldo A et al. Fam. Cancer. 2005;4:285-90; Hardt K et al. Fam. Cancer. 2011 Jun;10:273-84; Plummer JM et al. Can J Surg. 2012 Oct;55:294-300; De Lellis L et al. PLoS ONE. 2013 Nov;8:e81194). In our internal laboratory cohort, p.P640S was identified in a proband whose colorectal cancer exhibited microsatellite instability and absent MLH1 and PMS2 on IHC (Ambry internal data). In addition, this alteration has been seen in three unrelated probands meeting revised Bethesda criteria (Park K et al. Lab Med Online. 2018 Oct;8(4):156-166).<span style="font-family:noto sans,sans-serif; font-size:13.3333px"> Studies in yeast-based assays have shown this alteration results in reduced function and decreased relative MLH1 expression in a human cell line (Hardt K et al. Fam. Cancer. 2011 Jun;10:273-84). In an in vitro MMR complementation assay, this alteration had approximately 80% relative repair activity and also had reduced MLH1 expression (approximately 30% of wild type) in a human cell line (Hinrichsen I et al. Clin. Cancer Res. 2013 May;19:2432-41). Based on internal structure analysis, this variant is part of a structured region with known function and is more destabilizing than known likely pathogenic variants in the region (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analysis (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193959 SCV001363155 likely pathogenic Hereditary nonpolyposis colon cancer 2019-05-14 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1918C>T (p.Pro640Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251338 control chromosomes (gnomAD). c.1918C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (e.g. Giraldo_2005, Kang_2015, Shin_2004, Woo_2014), where in one family co-segregation with the disease was observed (Giraldo_2005), and in several cases microsatellite instable tumor and the loss of MLH1 protein was indicated (Kang_2015, Plummer_2012, and in the UMD database). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant had no impact on splicing (Tournier_2008), however the variant protein had decreased stability, impaired interaction with PMS2 and exhibited about 30% repair activity compared to wild type (Hardt_2011, Hinrichsen_2013). Three submitters, have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as likely pathogenic (2x) and VUS (1x). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354000 SCV000592427 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Pro640Ser variant was previously reported in 2/238 proband chromosomes (frequency of 0.006) in individuals with HNPCC or colorectal cancer (Giraldo_2005_16341804, Shin_2004_15365995), no controls were included in these studies. The p.Pro640 residue is conserved across mammals and lower species and computational analyses (Polyphen2, SIFT, AlignGVGD) suggest that the p.Pro640Ser variant may impact the protein with 3 out of 3 programs predicting pathogenicity. However, this information alone is not predictive enough to assume pathogenicity. An investigation of 23 MLH1 missense variants identified in families from the German HNPCC consortium by two functional in vivo assays in yeast concluded that p.Pro640Ser has a potential deleterious functional outcome (Hardt_2011_21404117). This variant occurs in the protein interaction domain and the p.Pro640Ser varaint also displayed a reduced capacity to interact with hMsh2 (Sun_2002_ 12414623). In addition, this variant was demonstrated to segregate in 3 affected Lynch syndrome family members (Giraldo_2005_16341804), suggesting this variant is pathogenic. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.

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