Submissions for variant NM_000249.4(MLH1):c.382G>A (p.Ala128Thr)

dbSNP: rs63750866

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000792046	SCV000931318	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-02-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 128 of the MLH1 protein (p.Ala128Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 11112663). This variant is also known as c.381G>A. ClinVar contains an entry for this variant (Variation ID: 639289). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Ala128 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9218993, 24362816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Diagnostics, LLC DBA Color Health	RCV001185870	SCV001352179	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-24	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 128 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome, described as c.381G>A (PMID: 11112663). This variant has been identified in 1/251284 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.382G>C (p.Ala128Pro), is considered to be disease-causing (ClinVar variation ID: 90199), 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.
Ambry Genetics	RCV001185870	SCV003858872	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing	The p.A128T variant (also known as c.382G>A), located in coding exon 5 of the MLH1 gene, results from a G to A substitution at nucleotide position 382. The alanine at codon 128 is replaced by threonine, an amino acid with similar properties. 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.
All of Us Research Program, National Institutes of Health	RCV004001560	SCV004835279	uncertain significance	Lynch syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 128 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome, described as c.381G>A (PMID: 11112663). This variant has been identified in 1/251284 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.382G>C (p.Ala128Pro), is considered to be disease-causing (ClinVar variation ID: 90199), 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.