Submissions for variant NM_000249.4(MLH1):c.848A>G (p.Tyr283Cys)

gnomAD frequency: 0.00001  dbSNP: rs201931669

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223129	SCV000277270	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-15	criteria provided, single submitter	clinical testing	The p.Y283C variant (also known as c.848A>G), located in coding exon 10 of the MLH1 gene, results from an A to G substitution at nucleotide position 848. The tyrosine at codon 283 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000588139	SCV000570504	uncertain significance	not provided	2022-09-23	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; Observed in individuals with breast or colorectal cancer (Akcay et al., 2020); This variant is associated with the following publications: (PMID: 22753075, 33980423, 32658311)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551542	SCV000625202	benign	Hereditary nonpolyposis colorectal neoplasms	2024-10-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797684	SCV000696185	uncertain significance	not specified	2021-11-30	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.848A>G (p.Tyr283Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like (IPR013507) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.848A>G has been reported in the literature in individuals affected with Colorectal Cancer or Breast Cancer (Akcay_2020, Solmaz_2021, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified 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	RCV000588139	SCV000889406	uncertain significance	not provided	2020-07-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001145069	SCV001305707	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000223129	SCV001353107	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-08	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 283 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 two individuals affected with colorectal cancer (PMID: 32658311) and in several individuals affected with breast cancer (PMID: 32658311, 33471991, 33980423). This variant has not been identified 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001797684	SCV002552444	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998017	SCV004840915	uncertain significance	Lynch syndrome	2024-03-25	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 283 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 two individuals affected with colorectal cancer (PMID: 32658311) and in several individuals affected with breast cancer (PMID: 32658311, 33471991, 33980423). This variant has not been identified 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.