Submissions for variant NM_000249.4(MLH1):c.1823C>T (p.Ala608Val)

dbSNP: rs267607864

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221100	SCV000277430	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	The p.A608V variant (also known as c.1823C>T), located in coding exon 16 of the MLH1 gene, results from a C to T substitution at nucleotide position 1823. The alanine at codon 608 is replaced by valine, an amino acid with similar properties. A different amino acid change at the same position (p.A608D), has been identified in Chinese and Norwegian Lynch syndrome kindreds (Sheng JQ et al, Cytogenet. Genome Res. 2008; 122(1):22-7; Sjursen W et al, J. Med. Genet. 2010 Sep; 47(9):579-85). 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.
Invitae	RCV000474071	SCV000543641	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-07-31	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MLH1-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 233120). This variant is present in population databases (rs267607864, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 608 of the MLH1 protein (p.Ala608Val).
GeneDx	RCV000484604	SCV000571328	uncertain significance	not provided	2017-10-30	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.1823C>T at the cDNA level, p.Ala608Val (A608V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ala608Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ala608Val occurs at a position that is conserved across species and is located in the regions of interaction with PMS2, MLH3, PMS1, and EXO1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Ala608Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000221100	SCV001351189	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462512	SCV004195103	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-09-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998029	SCV004843219	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV001824697	SCV002075011	not provided	Familial colorectal cancer		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 08-12-2020 by Lab or GTR ID 506138. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.