ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1103C>T (p.Ser368Leu) (rs201673334)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162449 SCV000212802 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-10 criteria provided, single submitter clinical testing The p.S368L variant (also known as c.1103C>T), located in coding exon 12 of the MLH1 gene, results from a C to T substitution at nucleotide position 1103. The serine at codon 368 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000476166 SCV000543561 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-04-12 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 368 of the MLH1 protein (p.Ser368Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs201673334, ExAC 0.03%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 183738). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000483837 SCV000571090 uncertain significance not provided 2018-03-14 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1103C>T at the cDNA level, p.Ser368Leu (S368L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has not, to our knowledge, been published in the literature as a germline pathogenic or benign variant. MLH1 Ser368Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Ser368Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV000758575 SCV000887317 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.1103C>T has a 14.8% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Color Health, Inc RCV000162449 SCV000911262 likely benign Hereditary cancer-predisposing syndrome 2017-06-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000483837 SCV001552494 uncertain significance not provided no assertion criteria provided clinical testing The MLH1 p.Ser368Leu variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs201673334) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, and GeneDx; and as likely benign by Color). The variant was identified in control databases in 6 of 276576 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 6 of 18846 chromosomes (freq: 0.0003), while the variant was not observed in the African, Other, Latino, European (Non-Finnish), Ashkenazi Jewish, European (Finnish), or South Asian populations. The variant was identified in our laboratory with a co-occurring, pathogenic POLE variant (c.6747+1G>A, r.spl?), increasing the likelihood that the p.Ser368Leu variant does not have clinical significance. The p.Ser368 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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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