Submissions for variant NM_000249.4(MLH1):c.1945C>T (p.Pro649Ser)

gnomAD frequency: 0.00001  dbSNP: rs1280930048

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000688390	SCV000816000	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 649 of the MLH1 protein (p.Pro649Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 568133). 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 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.
Ambry Genetics	RCV001013801	SCV001174431	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-14	criteria provided, single submitter	clinical testing	The p.P649S variant (also known as c.1945C>T), located in coding exon 17 of the MLH1 gene, results from a C to T substitution at nucleotide position 1945. The proline at codon 649 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284502	SCV001470331	uncertain significance	not provided	2019-10-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001284502	SCV004168210	uncertain significance	not provided	2023-05-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22949387, 22753075, 12799449, 20533529)
All of Us Research Program, National Institutes of Health	RCV004004281	SCV004843243	uncertain significance	Lynch syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 649 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 MLH1-related disorders in the literature. This variant has been identified in 1/251294 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.