Submissions for variant NM_000249.4(MLH1):c.739T>G (p.Ser247Ala)

gnomAD frequency: 0.00001  dbSNP: rs63750948

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629785	SCV000750741	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001026384	SCV001188754	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-28	criteria provided, single submitter	clinical testing	The p.S247A variant (also known as c.739T>G), located in coding exon 9 of the MLH1 gene, results from a T to G substitution at nucleotide position 739. The serine at codon 247 is replaced by alanine, an amino acid with similar properties. This amino acid position is 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320096	SCV004024340	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001026384	SCV004359201	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with alanine at codon 247 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 9/251274 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.739T>C (p.Ser247Pro), is considered to be disease-causing (ClinVar variation ID: 126985), suggesting that this position is important for the protein function. 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.
All of Us Research Program, National Institutes of Health	RCV003997209	SCV004836921	uncertain significance	Lynch syndrome	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with alanine at codon 247 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 9/251274 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.739T>C (p.Ser247Pro), is considered to be disease-causing (ClinVar variation ID: 126985), suggesting that this position is important for the protein function. 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.
Harris Lab, University of Minnesota	RCV000114847	SCV000148742	not provided	not provided		no assertion provided	not provided