Submissions for variant NM_000249.4(MLH1):c.622C>T (p.Pro208Ser)

gnomAD frequency: 0.00001  dbSNP: rs587781509

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129486	SCV000184257	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	The p.P208S variant (also known as c.622C>T), located in coding exon 8 of the MLH1 gene, results from a C to T substitution at nucleotide position 622. The proline at codon 208 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000212523	SCV000211094	uncertain significance	not provided	2018-08-28	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.622C>T at the cDNA level, p.Pro208Ser (P208S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Pro208Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (Andersen 2012). 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 Pro208Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000204556	SCV000260124	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-06-04	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 141121). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (rs587781509, gnomAD 0.002%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 208 of the MLH1 protein (p.Pro208Ser).
Color Diagnostics, LLC DBA Color Health	RCV000129486	SCV000904053	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-04	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 208 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with Lynch syndrome or Lynch syndrome-associated cancer in the literature. This variant has been identified in 2/251228 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260299	SCV001437220	uncertain significance	not specified	2022-03-24	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.622C>T (p.Pro208Ser) 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 allele was found at a frequency of 8e-06 in 251228 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.622C>T has been reported in the literature in one individual affected with T-cell acute lymphoblastic leukemia (Richter-Pechaska_2017), and in both breast cancer cases and controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212523	SCV002009355	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001260299	SCV004024897	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997506	SCV004835306	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 208 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with Lynch syndrome or Lynch syndrome-associated cancer in the literature. This variant has been identified in 2/251228 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.