Submissions for variant NM_000249.4(MLH1):c.976G>A (p.Val326Met)

gnomAD frequency: 0.00001  dbSNP: rs730881739

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160530	SCV000211099	uncertain significance	not provided	2024-08-08	criteria provided, single submitter	clinical testing	Observed in a patient with colorectal cancer (PMID: 29212164); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22753075, 29212164, 36845387)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469188	SCV000543626	benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566682	SCV000662048	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	The p.V326M variant (also known as c.976G>A), located in coding exon 11 of the MLH1 gene, results from a G to A substitution at nucleotide position 976. The valine at codon 326 is replaced by methionine, an amino acid with highly similar properties. This alteration was identified in a cohort of familial colorectal cancer patients undergoing multigene panel testing (Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000566682	SCV000684886	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 326 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 observed in an individual affected with colon cancer, whose tumor showed microsatellite stability (PMID: 29212164). This variant has been identified in 1/251374 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.
PreventionGenetics, part of Exact Sciences	RCV003398824	SCV004104717	uncertain significance	MLH1-related disorder	2023-08-01	criteria provided, single submitter	clinical testing	The MLH1 c.976G>A variant is predicted to result in the amino acid substitution p.Val326Met. This variant was reported as a variant of uncertain significance in a large cohort of individuals with colon cancer (Raskin et al. 2017. PubMed ID: 29212164, supplementary data). This variant was also described in a patient with suspected Lynch syndrome; however, pathogenic variants were identified in other genes in that individual (Infante et al. 2022. PubMed ID: 36232793). This variant is reported in 1 of ~251,000 alleles in the gnomAD public population database (http://gnomad.broadinstitute.org/variant/3-37061892-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Myriad Genetics, Inc.	RCV003453266	SCV004189557	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-11-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].