Submissions for variant NM_000249.4(MLH1):c.1348G>T (p.Asp450Tyr)

dbSNP: rs752622244

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216865	SCV000275780	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-08	criteria provided, single submitter	clinical testing	The p.D450Y variant (also known as c.1348G>T), located in coding exon 12 of the MLH1 gene, results from a G to T substitution at nucleotide position 1348. The aspartic acid at codon 450 is replaced by tyrosine, an amino acid with highly dissimilar 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.
Invitae	RCV000230653	SCV000284015	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 450 of the MLH1 protein (p.Asp450Tyr). This variant is present in population databases (rs752622244, gnomAD 0.006%). This missense change has been observed in individual(s) with breast and pancreatic cancer (PMID: 35171259, 35449176). ClinVar contains an entry for this variant (Variation ID: 231818). 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.
Color Diagnostics, LLC DBA Color Health	RCV000216865	SCV000684738	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-04	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 450 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 1/251098 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.
GeneDx	RCV001770179	SCV001992945	uncertain significance	not provided	2023-04-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22753075)
All of Us Research Program, National Institutes of Health	RCV003997928	SCV004840994	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 450 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 1/251098 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.