Submissions for variant NM_000249.4(MLH1):c.1103C>T (p.Ser368Leu)

gnomAD frequency: 0.00001  dbSNP: rs201673334

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162449	SCV000212802	likely benign	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000476166	SCV000543561	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
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 Diagnostics, LLC DBA Color Health	RCV000162449	SCV000911262	likely benign	Hereditary cancer-predisposing syndrome	2017-06-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000483837	SCV002009381	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462116	SCV004190641	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-08-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483837	SCV004220057	likely benign	not provided	2023-08-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000758575	SCV004840953	likely benign	Lynch syndrome	2023-02-24	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.