Submissions for variant NM_000249.4(MLH1):c.2162A>G (p.Tyr721Cys)

gnomAD frequency: 0.00001  dbSNP: rs587778986

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212548	SCV000211121	uncertain significance	not provided	2023-03-03	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; Identified in a patient with suspected hereditary colorectal cancer whose tumor demonstrated loss of MLH1 and PMS2 protein expression (Arnold et al., 2020); This variant is associated with the following publications: (PMID: 24362816, 26580448, 12799449, 20533529, 22753075, 31822864)
Ambry Genetics	RCV000160544	SCV000216852	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-16	criteria provided, single submitter	clinical testing	The p.Y721C variant (also known as c.2162A>G), located in coding exon 19 of the MLH1 gene, results from an A to G substitution at nucleotide position 2162. The tyrosine at codon 721 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients, who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with acute lymphoblastic leukemia (ALL) (Zhang J et al. N. Engl. J. Med. 2015 Dec;373:2336-2346). This alteration was also identified in a cohort of unexplained cases of suspected Lynch syndrome (Arnold AM et al. Eur J Hum Genet, 2020 05;28:597-608). This amino acid position is well 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.
Counsyl	RCV000409675	SCV000488822	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-06-23	criteria provided, single submitter	clinical testing
Invitae	RCV000524278	SCV000543648	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 721 of the MLH1 protein (p.Tyr721Cys). This variant is present in population databases (rs587778986, gnomAD 0.006%). This missense change has been observed in individual(s) with acute lymphocytic leukemia and/or clinical features of Lynch syndrome (PMID: 26580448, 31822864, 35449176). ClinVar contains an entry for this variant (Variation ID: 90078). 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	RCV000160544	SCV000908656	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 721 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 suspected of Lynch syndrome (PMID: 31822864). This variant has been identified in 3/251160 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781540	SCV000919657	uncertain significance	not specified	2019-10-10	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.2162A>G (p.Tyr721Cys) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251160 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, there are no reports of c.2162A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating an impact of the variant on protein function in the literature. The variant has been reported in one individual with acute lymphocytic leukemia without strong evidence for causality (Zhang_2015). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212548	SCV002046282	uncertain significance	not provided	2023-06-16	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35449176 (2022) and suspected Lynch syndrome (PMID: 31822864 (2020)). This variant has also been reported in an individual with acute lymphocytic leukemia (PMID: 26580448 (2015)). The frequency of this variant in the general population, 0.000012 (3/251160 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV002483123	SCV002788436	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2022-03-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409675	SCV004018194	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	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: 25085752].
PreventionGenetics, part of Exact Sciences	RCV003390768	SCV004120784	uncertain significance	MLH1-related disorder	2022-08-30	criteria provided, single submitter	clinical testing	The MLH1 c.2162A>G variant is predicted to result in the amino acid substitution p.Tyr721Cys. This variant was reported in an individual with non-polyposis colorectal cancer, although pathogenicity was not established (Arnold et al 2020. PubMed ID: 31822864). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-37092035-A-G) and is listed in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/90078/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000409675	SCV004195017	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997125	SCV004843290	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 721 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 affected with acute lymphoblastic leukemia (PMID: 26580448). This variant has been identified in 3/251160 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.
GenomeConnect - Invitae Patient Insights Network	RCV000212548	SCV001716324	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-06-2015 by 61756. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory.