Submissions for variant NM_000249.4(MLH1):c.1136A>T (p.Tyr379Phe)

dbSNP: rs143009528

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212530	SCV000149360	uncertain significance	not provided	2023-08-29	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; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000115451	SCV000185286	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-28	criteria provided, single submitter	clinical testing	The p.Y379F variant (also known as c.1136A>T), located in coding exon 12 of the MLH1 gene, results from an A to T substitution at nucleotide position 1136. The tyrosine at codon 379 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212530	SCV001134286	uncertain significance	not provided	2018-12-03	criteria provided, single submitter	clinical testing
Invitae	RCV001063775	SCV001228636	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115451	SCV001351181	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-15	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with phenylalanine at codon 379 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/282670 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.
Sema4, Sema4	RCV000115451	SCV002528626	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-18	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265606	SCV002547921	uncertain significance	not specified	2022-05-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407496	SCV004113279	uncertain significance	MLH1-related disorder	2023-06-20	criteria provided, single submitter	clinical testing	The MLH1 c.1136A>T variant is predicted to result in the amino acid substitution p.Tyr379Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-37067225-A-T) and has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127608/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003997258	SCV004840961	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with phenylalanine at codon 379 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). 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/282670 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.