Submissions for variant NM_000249.4(MLH1):c.1960C>T (p.Pro654Ser)

dbSNP: rs1559591314

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758635	SCV000887393	likely benign	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.1960C>T has a 2.3% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics	RCV002422642	SCV002718869	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	clinical testing	The p.P654S variant (also known as c.1960C>T), located in coding exon 17 of the MLH1 gene, results from a C to T substitution at nucleotide position 1960. The proline at codon 654 is replaced by serine, an amino acid with similar properties. This variant has been detected as somatic in a colon cancer patient in conjunction with a somatic MLH1 mutation and MLH1 loss of heterozygosity (Shirts BH et al. Am J Hum Genet. 2018 Jul 5;103(1):19-29). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV003117543	SCV003789031	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-25	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. This variant disrupts the p.Pro654 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16083711, 17510385, 20533529, 21404117). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 619552). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 654 of the MLH1 protein (p.Pro654Ser).