Submissions for variant NM_000249.4(MLH1):c.454G>A (p.Val152Met)

gnomAD frequency: 0.00001  dbSNP: rs748417604

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163977	SCV000214577	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-27	criteria provided, single submitter	clinical testing	The p.V152M variant (also known as c.454G>A), located in coding exon 6 of the MLH1 gene, results from a G to A substitution at nucleotide position 454. The valine at codon 152 is replaced by methionine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 6. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC) (Ambry internal data). In one study, this variant was observed in 1/626 Northern European patients with colorectal cancer diagnosed before age 56, who had at least one first-degree relative with colorectal cancer (Chubb D et al. J. Clin. Oncol. 2015 Feb;33(5):426-32). 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.
GeneDx	RCV000222401	SCV000279325	uncertain significance	not provided	2018-10-26	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.454G>A at the cDNA level, p.Val152Met (V152M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has been observed in at least one individual with a personal and family history of colorectal cancer (Chubb 2015). MLH1 Val152Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Val152Met occurs at a position that is conserved across species and is located within the N-terminal ATPase domain (Anderson 2012). Protein based in silico analyses predict that this variant is probably damaging to protein structure and function while splicing based models predict this variant to either weaken or destroy the natural splice acceptor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether MLH1 Val152Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000540116	SCV000625164	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 152 of the MLH1 protein (p.Val152Met). This variant is present in population databases (rs748417604, gnomAD 0.002%). This missense change has been observed in individual(s) with colorectal cancer and esophageal cancer (PMID: 25559809, 30833958). ClinVar contains an entry for this variant (Variation ID: 184683). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV000163977	SCV000689887	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 152 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 individuals affected with colorectal cancer (PMID: 25559809), esophageal squamous cell carcinoma (PMID: 30833958), or breast cancer (PMID 34359559). This variant has been identified in 2/251266 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.
Genetics and Molecular Pathology, SA Pathology	RCV003447510	SCV004175483	uncertain significance	Muir-Torré syndrome	2023-04-13	criteria provided, single submitter	clinical testing	The MLH1 c.454G>A variant is classified as VUS (PS4_Supporting, PM2, PP3) The MLH1 c.454G>A variant is located in a splice region. The MLH1 c.454G>A variant is a single nucleotide change in exon 6/19 of the MLH1 gene, which is predicted to change the amino acid valine at position 152 in the protein to methionine. The variant has been reported in a patient with esophageal cancer and another with colon cancer (PMID:25559809, PMID:30833958) (PS4_Supporting). This variant is absent from population databases (PM2). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs748417604) and in the HGMD database (CM1913018). It has been reported as Uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 184683).
All of Us Research Program, National Institutes of Health	RCV003995305	SCV004835288	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 152 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 individuals affected with colorectal cancer (PMID: 25559809), esophageal squamous cell carcinoma (PMID: 30833958), or breast cancer (PMID 34359559). This variant has been identified in 2/251266 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.