Submissions for variant NM_000249.4(MLH1):c.2074T>C (p.Ser692Pro)

dbSNP: rs587779957

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000680201	SCV000807665	benign	Lynch syndrome 1	2018-06-13	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability < 0.001 (0.00014)
GeneDx	RCV000115471	SCV000149380	likely benign	not provided	2018-11-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15713769)
Invitae	RCV000548695	SCV000625122	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-09-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181644	SCV001346833	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 692 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 15713769). This variant has also been identified in 1/251112 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	RCV002509223	SCV002819786	uncertain significance	not specified	2022-12-24	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.2074T>C (p.Ser692Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251112 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2074T>C has been reported in the literature as a VUS in at-least one individual among colorectal cancer cases from HNPCC Amsterdam 1 criteria families with defective mismatch repair and protein expression reported as - MLH1 and MSH2 intact (example, Casey_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories and an expert panel (INSIGHT) reported the variant with conflicting assessments (VUS, n=2; LB/B, n=2 including the expert panel). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997265	SCV004843268	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 692 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 15713769). This variant has also been identified in 1/251112 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.