Submissions for variant NM_000249.4(MLH1):c.652T>C (p.Ser218Pro)

gnomAD frequency: 0.00001  dbSNP: rs750650349

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000475778	SCV000543604	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564654	SCV000662013	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-25	criteria provided, single submitter	clinical testing	The p.S218P variant (also known as c.652T>C), located in coding exon 8 of the MLH1 gene, results from a T to C substitution at nucleotide position 652. The serine at codon 218 is replaced by proline, an amino acid with similar properties. This alteration has been reported in 1/400 individuals in a non-cancer related whole exome sequencing cohort assessed for secondary findings in hereditary cancer predisposition genes (Kraemer D et al. Swiss Med Wkly. 2019 Aug;149:w20092). This amino acid position is not 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.
Color Diagnostics, LLC DBA Color Health	RCV000564654	SCV000911477	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 218 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 MLH1-related disorders in the literature. This variant has been identified in 2/251136 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.
Mendelics	RCV000987155	SCV001136382	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280631	SCV001467862	uncertain significance	not specified	2020-12-03	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.652T>C (p.Ser218Pro) results in a non-conservative amino acid change in 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 8e-06 in 251136 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.652T>C has been reported in the literature in an unaffected individual (Kraemer_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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.
Baylor Genetics	RCV000987155	SCV004192977	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-06-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000657	SCV004840886	uncertain significance	Lynch syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 218 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 MLH1-related disorders in the literature. This variant has been identified in 2/251136 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.