rs63750430
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM5PP3_ModerateBP6
The NM_000249.4(MLH1):c.1154G>A(p.Arg385His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,526 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R385C) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000032 ( 1 hom. )
Consequence
MLH1
NM_000249.4 missense
NM_000249.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 9.13
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-37025751-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.871
BP6
Variant 3-37025752-G-A is Benign according to our data. Variant chr3-37025752-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 140759.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Benign=2, Likely_benign=1}. Variant chr3-37025752-G-A is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000396 AC: 6AN: 151648Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251414Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135872
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GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461878Hom.: 1 Cov.: 34 AF XY: 0.0000413 AC XY: 30AN XY: 727242
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GnomAD4 genome 0.0000396 AC: 6AN: 151648Hom.: 0 Cov.: 31 AF XY: 0.0000405 AC XY: 3AN XY: 74034
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:13Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:5Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 10, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Oct 16, 2023 | The MLH1 c.1154G>A (p.Arg385His) missense change has a maximum subpopulation frequency of 0.019% 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 has been reported in one individual with Lynch syndrome-related colorectal cancer (PMID: 35223509), as well as in individuals with prostate cancer (PMID: 31248605), lung adenocarcinoma (PMID: 35280419), and familial breast/ovarian cancer (PMID: 30982232). 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. - |
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 14, 2023 | This variant is considered 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]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. - |
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 03, 2024 | The MLH1 c.1154G>A (p.Arg385His) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 30982232 (2019), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MLH1), 35264596 (2022), 35449176 (2022)), prostate cancer (PMID: 31248605 (2019)), colorectal cancer (PMID: 35223509 (2022)), gastric cancer (PMID: 36627197 (2023)), and another unspecified cancer (PMID: 31248605 (2020)). This variant is also found in reportedly healthy individuals (PMID: 32980694 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MLH1), 36243179 (2022)). The frequency of this variant in the general population, 0.0002 (6/30616 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 10, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate MLH1 protein expression and mismatch repair (MMR) activity similar to wildtype (PMID: 37224528); Observed in individuals with colorectal, breast, or other cancers, as well as in unaffected controls is a study of biliary tract cancer (PMID: 36243179, 27498913, 30982232, 35223509, 35264596, 36627197, 35449176); This variant is associated with the following publications: (PMID: 31391288, 27149842, 33042626, 31248605, 36215471, 27498913, 35223509, 30982232, 35264596, 36627197, 37224528, Abudabbous2023[CaseReport], 36243179, 35449176) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 11, 2020 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 17, 2023 | This missense variant replaces arginine with histidine at codon 385 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 observed in an individual affected with colorectal cancer (PMID: 35223509), an individual affected with Ewing sarcoma (PMID: 27498913), and individual affected with gastric cancer who also had a pathogenic variant in the ATM gene (PMID: 36627197), and in two unaffected individuals in a pancreatic case-control study (PMID: 32980694). This variant has been identified in 15/282582 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. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 14, 2022 | Variant summary: MLH1 c.1154G>A (p.Arg385His) results in a non-conservative amino acid change in 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 5.2e-05 in 251414 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (5.2e-05 vs 0.00071), allowing no conclusion about variant significance. c.1154G>A has been reported in the literature as a VUS in settings of multi-gene testing in at least one individual affected with Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch Syndrome, and in individuals affected with prostate and other cancers (e.g. Wang_2019, Wei_2019, Li_2021, Fanale_2022). These reports do not provide unequivocal conclusions about association of the variant with HNPCC/Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as VUS (n=9) and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Lynch syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 23, 2024 | This missense variant replaces arginine with histidine at codon 385 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). A functional study demonstrated this variant has no impact on protein expression or mismatch repair activity, with similar activity to wild type protein (PMID: 37224528). This variant has been observed in an individual affected with colorectal cancer (PMID: 35223509), an individual affected with Ewing sarcoma (PMID: 27498913), and individual affected with gastric cancer who also had a pathogenic variant in the ATM gene (PMID: 36627197), and in two unaffected individuals in a pancreatic case-control study (PMID: 32980694). This variant has been identified in 15/282582 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. - |
Lynch-like syndrome Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Constitutional Genetics Lab, Leon Berard Cancer Center | Jul 01, 2019 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2025 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;.;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at