Submissions for variant NM_000249.4(MLH1):c.1255A>G (p.Ile419Val)

dbSNP: rs781335662

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000542296	SCV000625052	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-05-02	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 455380). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 419 of the MLH1 protein (p.Ile419Val). This variant is present in population databases (rs781335662, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 28135048). 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.
Color Diagnostics, LLC DBA Color Health	RCV001805148	SCV002052612	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 419 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 5/251348 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.
Ambry Genetics	RCV001805148	SCV002680879	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-05	criteria provided, single submitter	clinical testing	The p.I419V variant (also known as c.1255A>G), located in coding exon 12 of the MLH1 gene, results from an A to G substitution at nucleotide position 1255. The isoleucine at codon 419 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly 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.
GeneDx	RCV003441911	SCV004169800	uncertain significance	not provided	2023-05-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with triple negative breast cancer (Liu et al., 2017); This variant is associated with the following publications: (PMID: 28135048, 22753075)
All of Us Research Program, National Institutes of Health	RCV004003709	SCV004840982	uncertain significance	Lynch syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 419 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 5/251348 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.