Submissions for variant NM_000249.4(MLH1):c.1148T>C (p.Met383Thr)

gnomAD frequency: 0.00004  dbSNP: rs141344760

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656861	SCV000149361	uncertain significance	not provided	2023-01-18	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 ovarian or colorectal cancer as well as unaffected controls (Pal et al., 2012; Iordache et al., 2018; Rosenthal et al., 2018); This variant is associated with the following publications: (PMID: 25637381, 28822769, 23047549, 26269718, 23729658, 30324682, 30267214, 33471991)
Ambry Genetics	RCV000115452	SCV000215984	likely benign	Hereditary cancer-predisposing syndrome	2023-06-08	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212532	SCV000539643	uncertain significance	not specified	2016-03-31	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD; Absent from ExAC with good coverage, but present in ESP?; ClinVar: 3 VUS
Invitae	RCV000459634	SCV000543625	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 383 of the MLH1 protein (p.Met383Thr). This variant is present in population databases (rs141344760, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer, lung cancer or colorectal cancer (PMID: 23047549, 30324682). ClinVar contains an entry for this variant (Variation ID: 127609). 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 not expected to disrupt MLH1 protein function with a negative 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.
Color Diagnostics, LLC DBA Color Health	RCV000115452	SCV000684717	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 383 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer or colorectal cancer (PMID: 23047549, 30324682, 31391288). This variant has been identified in 2/282658 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.
Counsyl	RCV000662617	SCV000785280	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-06-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212532	SCV003844602	uncertain significance	not specified	2023-09-14	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1148T>C (p.Met383Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three 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 251430 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1148T>C has been reported in the literature in individuals affected with ovarian cancer (Pal_2012) and colorectal cancer (Iordache_2018). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 30324682, 23047549). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=6) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000662617	SCV004018149	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000662617	SCV004195038	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997259	SCV004840963	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 383 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer or colorectal cancer (PMID: 23047549, 30324682, 31391288). This variant has been identified in 2/282658 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.
CSER _CC_NCGL, University of Washington	RCV000148622	SCV000190337	uncertain significance	Ovarian cancer	2014-06-01	no assertion criteria provided	research
Gharavi Laboratory, Columbia University	RCV000656861	SCV000920688	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV000656861	SCV001749346	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 07-14-2015 by GeneDx. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.