ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.19G>T (p.Val7Phe)

gnomAD frequency: 0.00011  dbSNP: rs730881746
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160549 SCV000211127 uncertain significance not provided 2022-02-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a family with Lynch syndrome (Lagerstedt-Robinson 2016); This variant is associated with the following publications: (PMID: 27601186, 22753075)
Labcorp Genetics (formerly Invitae), Labcorp RCV000703809 SCV000832728 benign Hereditary nonpolyposis colorectal neoplasms 2023-11-18 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001804884 SCV002053390 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-03 criteria provided, single submitter clinical testing This missense variant replaces valine with phenylalanine at codon 7 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 27601186) or an individual suspected of having Lynch syndrome (PMID: 32973888). This variant has been identified in 33/282876 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 RCV001804884 SCV002717783 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-19 criteria provided, single submitter clinical testing The p.V7F variant (also known as c.19G>T), located in coding exon 1 of the MLH1 gene, results from a G to T substitution at nucleotide position 19. The valine at codon 7 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was observed in a 32 year old male with Lynch-like syndrome (LLS) in a cohort of 81 patients with LLS and 47 patients with Lynch syndrome who all had mismatch repair deficient colorectal cancer (Xu Y et al. Front Genet, 2020 Aug;11:991). In addition, this alteration was reported in one Sweedish family who meet criteria for clinical testing for Lynch syndrome (Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835). 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.

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