Submissions for variant NM_000249.4(MLH1):c.1067C>T (p.Ser356Phe)

gnomAD frequency: 0.00003  dbSNP: rs749334262

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200267	SCV000254345	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 356 of the MLH1 protein (p.Ser356Phe). This variant is present in population databases (rs749334262, gnomAD 0.01%). This missense change has been observed in individual(s) with MLH1-related conditions (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 216329). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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	RCV000220017	SCV000277009	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-12	criteria provided, single submitter	clinical testing	The p.S356F variant (also known as c.1067C>T), located in coding exon 12 of the MLH1 gene, results from a C to T substitution at nucleotide position 1067. The serine at codon 356 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is not well 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.
GeneDx	RCV000482737	SCV000567887	uncertain significance	not provided	2023-07-24	criteria provided, single submitter	clinical testing	Not observed at a 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
Color Diagnostics, LLC DBA Color Health	RCV000220017	SCV002052630	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 356 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 hereditary cancer in the literature. This variant has been identified in 1/29432 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491943	SCV004240738	uncertain significance	Breast and/or ovarian cancer	2022-08-25	criteria provided, single submitter	clinical testing