Submissions for variant NM_000249.4(MLH1):c.1490G>A (p.Arg497Gln)

gnomAD frequency: 0.00001  dbSNP: rs754554026

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214903	SCV000279283	uncertain significance	not provided	2019-10-31	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as a germline pathogenic or benign variant to our knowledge; This variant is associated with the following publications: (PMID: 29596542, 22608206)
Invitae	RCV000462302	SCV000543565	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-08-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000774707	SCV000908632	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 497 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 MLH1-related disorders in the literature. This variant has been identified in 7/251480 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	RCV000774707	SCV001172248	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-08	criteria provided, single submitter	clinical testing	The p.R497Q variant (also known as c.1490G>A), located in coding exon 13 of the MLH1 gene, results from a G to A substitution at nucleotide position 1490. The arginine at codon 497 is replaced by glutamine, an amino acid with highly similar properties. This alteration was seen in 0/732 breast cancer patients, 1/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264530	SCV001442734	uncertain significance	not specified	2023-09-03	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1490G>A (p.Arg497Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251480 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1490G>A in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=4; LB, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003998618	SCV004841025	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 497 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual suspected of having hereditary breast/ovarian cancer (PMID: 34359559). This variant has been identified in 7/251480 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.