Submissions for variant NM_000249.4(MLH1):c.988A>G (p.Ile330Val)

dbSNP: rs878853796

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226414	SCV000284085	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-23	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 237354). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 330 of the MLH1 protein (p.Ile330Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mismatch repair deficiency (PMID: 30877237).
Ambry Genetics	RCV000561417	SCV000662064	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The p.I330V variant (also known as c.988A>G), located in coding exon 11 of the MLH1 gene, results from an A to G substitution at nucleotide position 988. The isoleucine at codon 330 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in an individual with colorectal cancer diagnosed at age 65 that demonstrated loss of MSH2 and MSH6 on immunohistochemistry (Pearlman R et al. J Med Genet, 2019 Jul;56:462-470). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000561417	SCV000911678	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 330 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 been reported in an individual affected with colorectal cancer that exhibited high microsatellite instability and loss of MSH2 and MSH6 proteins by immunohistochemistry analyses (PMID: 30877237). This variant has not been identified 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.
All of Us Research Program, National Institutes of Health	RCV003998748	SCV004840936	uncertain significance	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 330 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 been reported in an individual affected with colorectal cancer that exhibited high microsatellite instability and loss of MSH2 and MSH6 proteins by immunohistochemistry analyses (PMID: 30877237). This variant has not been identified 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.