Submissions for variant NM_000249.4(MLH1):c.919G>A (p.Val307Met)

dbSNP: rs786202196

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164898	SCV000215585	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-08	criteria provided, single submitter	clinical testing	The p.V307M variant (also known as c.919G>A), located in coding exon 11 of the MLH1 gene, results from a G to A substitution at nucleotide position 919. The valine at codon 307 is replaced by methionine, an amino acid with highly similar properties. 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	RCV000699276	SCV000827979	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-07-13	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 307 of the MLH1 protein (p.Val307Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with advanced cancer of an unspecified type (PMID: 28873162). ClinVar contains an entry for this variant (Variation ID: 185469). 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. 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	RCV000164898	SCV000908616	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 307 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 an individual with an unspecified advanced cancer (PMID: 28873162). 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.
GeneDx	RCV001548388	SCV001768290	uncertain significance	not provided	2023-03-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with advanced cancer undergoing multi-gene panel testing (Mandelker et al., 2017); This variant is associated with the following publications: (PMID: 22753075, 28873162)
Sema4, Sema4	RCV000164898	SCV002528789	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003995376	SCV004840921	uncertain significance	Lynch syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 307 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 an individual with an unspecified advanced cancer (PMID: 28873162). 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.