Submissions for variant NM_000249.4(MLH1):c.541G>A (p.Gly181Ser)

gnomAD frequency: 0.00001  dbSNP: rs1064795694

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482251	SCV000571728	uncertain significance	not provided	2016-09-18	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.541G>A at the cDNA level, p.Gly181Ser (G181S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Gly181Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Gly181Ser occurs at a position that is conserved in mammals and is not located in a known functional domain (Raevaara 2005, Hardt 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Gly181Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000771539	SCV000904098	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000771539	SCV001186033	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-15	criteria provided, single submitter	clinical testing	The p.G181S variant (also known as c.541G>A), located in coding exon 6 of the MLH1 gene, results from a G to A substitution at nucleotide position 541. The glycine at codon 181 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001338323	SCV001531984	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 181 of the MLH1 protein (p.Gly181Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal or family history of breast cancer (PMID: 32986223, 35980532). ClinVar contains an entry for this variant (Variation ID: 422298). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MLH1 function with a negative predictive value of 95%. 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000482251	SCV002009358	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222526	SCV002500377	uncertain significance	not specified	2022-03-14	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.541G>A (p.Gly181Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251428 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.541G>A has been reported in the literature in individuals affected with breast cancer without strong evidence for causality (example: Dorling_2021 and Bandeira_2020), as well as unaffected controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all aboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002222526	SCV002552430	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing