Submissions for variant NM_000249.4(MLH1):c.2051A>G (p.Tyr684Cys)

dbSNP: rs267607886

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524271	SCV000254366	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-20	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 684 of the MLH1 protein (p.Tyr684Cys). This variant is present in population databases (rs267607886, gnomAD 0.01%). This missense change has been observed in individual(s) with colon cancer and/or peritoneal cancer (PMID: 18566915, 30093976). ClinVar contains an entry for this variant (Variation ID: 90013). 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) performed at Invitae indicates that this missense variant is expected to disrupt 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.
GeneDx	RCV000478138	SCV000565166	uncertain significance	not provided	2021-04-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with peritoneal cancer, leukemia, or familial colorectal cancer (Nilbert 2009, Zhang 2015, Chan 2018); This variant is associated with the following publications: (PMID: 25801821, 33309985, 26580448, 18566915, 30093976)
Ambry Genetics	RCV000562804	SCV000669600	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-22	criteria provided, single submitter	clinical testing	The p.Y684C variant (also known as c.2051A>G), located in coding exon 18 of the MLH1 gene, results from an A to G substitution at nucleotide position 2051. The tyrosine at codon 684 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a Danish cohort of individuals with colorectal cancer (Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83), in a Chinese patient with peritoneal cancer who had a family history of stomach and breast cancer (Chan GHJ et al. Oncotarget 2018 Jul;9(55):30649-30660), in a cohort of 431 patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium (Lee YR et al. N Engl J Med, 2020 05;382:2103-2116), and in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with hyperdiploid ALL (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). 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.
Counsyl	RCV000662677	SCV000785385	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-07-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000562804	SCV000911480	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 684 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 Lynch syndrome (PMID: 18566915) and an individual affected with peritoneal cancer (PMID: 30093976). This variant has been identified in 6/282622 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.
Myriad Genetics, Inc.	RCV000662677	SCV004018193	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV003997123	SCV004843260	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 684 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 Lynch syndrome (PMID: 18566915) and an individual affected with peritoneal cancer (PMID: 30093976). This variant has been identified in 6/282622 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.