Submissions for variant NM_000249.4(MLH1):c.925C>T (p.Pro309Ser)

gnomAD frequency: 0.00002  dbSNP: rs267607808

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684787	SCV000259481	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 309 of the MLH1 protein (p.Pro309Ser). This variant is present in population databases (rs267607808, gnomAD 0.004%). This missense change has been observed in individual(s) with colon cancer (PMID: 18033691). ClinVar contains an entry for this variant (Variation ID: 90444). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MLH1 function with a positive predictive value of 95%. 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	RCV000486267	SCV000567201	uncertain significance	not provided	2020-12-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18033691, 25871441)
Ambry Genetics	RCV000574268	SCV000662018	likely benign	Hereditary cancer-predisposing syndrome	2019-01-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000574268	SCV000689930	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 309 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 colorectal cancer whose tumor displayed microsatellite stability and intact MLH1, MSH2, and MSH6 protein via immunohistochemistry analysis (PMID: 18033691). This variant has been identified in 4/251422 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486267	SCV002046768	uncertain significance	not provided	2021-03-22	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325180	SCV004031189	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-06-15	criteria provided, single submitter	clinical testing	The MLH1 c.925C>T (p.Pro309Ser) missense change has a maximum subpopulation frequency of 0.0035% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant was reported in an individual with microsatellite stable colorectal cancer (PMID: 18033691). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV003325180	SCV004195021	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-03-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000486267	SCV004226063	uncertain significance	not provided	2022-02-23	criteria provided, single submitter	clinical testing	PP3, PM2
All of Us Research Program, National Institutes of Health	RCV003997139	SCV004840923	uncertain significance	Lynch syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 309 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 colorectal cancer whose tumor displayed microsatellite stability and intact MLH1, MSH2, and MSH6 protein via immunohistochemistry analysis (PMID: 18033691). This variant has been identified in 4/251422 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	RCV004799779	SCV005423466	uncertain significance	not specified	2024-10-03	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.925C>T (p.Pro309Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251422 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.925C>T has been reported in the literature in individuals affected with colorectal cancer and acute myeloid leukemia (AML) (e.g., Barnetson_2008, Umeda_2022). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18033691, 35176137). ClinVar contains an entry for this variant (Variation ID: 90444). Based on the evidence outlined above, the variant was classified as uncertain significance.