rs28756986
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001040108.2(MLH3):c.1870G>C(p.Glu624Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00964 in 1,614,018 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0075 ( 6 hom., cov: 33)
Exomes 𝑓: 0.0099 ( 89 hom. )
Consequence
MLH3
NM_001040108.2 missense
NM_001040108.2 missense
Scores
5
13
Clinical Significance
Conservation
PhyloP100: 1.23
Genes affected
MLH3 (HGNC:7128): (mutL homolog 3) This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0042276084).
BP6
?
Variant 14-75047786-C-G is Benign according to our data. Variant chr14-75047786-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 5560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75047786-C-G is described in Lovd as [Pathogenic]. Variant chr14-75047786-C-G is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00745 (1135/152320) while in subpopulation NFE AF= 0.0121 (823/68032). AF 95% confidence interval is 0.0114. There are 6 homozygotes in gnomad4. There are 528 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 1135 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH3 | NM_001040108.2 | c.1870G>C | p.Glu624Gln | missense_variant | 2/13 | ENST00000355774.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH3 | ENST00000355774.7 | c.1870G>C | p.Glu624Gln | missense_variant | 2/13 | 5 | NM_001040108.2 | P1 | |
MLH3 | ENST00000380968.6 | c.1870G>C | p.Glu624Gln | missense_variant | 2/12 | 1 | |||
MLH3 | ENST00000556257.5 | c.1870G>C | p.Glu624Gln | missense_variant | 2/7 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00745 AC: 1134AN: 152202Hom.: 6 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00716 AC: 1799AN: 251246Hom.: 8 AF XY: 0.00712 AC XY: 967AN XY: 135764
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GnomAD4 exome AF: 0.00987 AC: 14420AN: 1461698Hom.: 89 Cov.: 35 AF XY: 0.00959 AC XY: 6976AN XY: 727156
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GnomAD4 genome ? AF: 0.00745 AC: 1135AN: 152320Hom.: 6 Cov.: 33 AF XY: 0.00709 AC XY: 528AN XY: 74492
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Asia WGS
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 7 Uncertain:1Benign:3
Uncertain significance, no assertion criteria provided | literature only | OMIM | Apr 01, 2009 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 01, 2020 | This alteration is classified as 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 28, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MLH3 p.Glu624Gln variant was identified in 7 of 1036 proband chromosomes (frequency: 0.00676) from individuals or families with suspected Lynch syndrome or colorectal cancer (Wu_2001_PMID: 11586295, Liu_2003_PMID: 12702580, Rohlin_2017_PMID: 27696107, & Hienonen_2003_PMID: 12800209). The variant was also identified in the following databases: dbSNP (ID: rs28756986) as “With Uncertain significance allele”, ClinVar (classified as benign by Invitae with the associated phenotype of Hereditary nonpolyposis colorectal cancer type 7/MLH3-Related Lynch Syndrome; and uncertain significance by OMIM), and LOVD 3.0 (multiple entries with classifications of VUS, likely benign, and pathogenic). The variant was not identified in the Cosmic database. The variant was identified in control databases in 2120 of 282638 chromosomes (11 homozygous) at a frequency of 0.007501 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 1516 of 129054 chromosomes (freq: 0.01175), European (Finnish) in 201 of 25108 chromosomes (freq: 0.008005), Other in 49 of 7218 chromosomes (freq: 0.006789), Latino in 210 of 35396 chromosomes (freq: 0.005933), Ashkenazi Jewish in 39 of 10362 chromosomes (freq: 0.003764), African in 51 of 24968 chromosomes (freq: 0.002043), South Asian in 53 of 30584 chromosomes (freq: 0.001733) and East Asian in 1 of 19948 chromosomes (freq: 0.00005). To clarify the role of the p.E624Q, in vitro functional studies were conducted transfecting wildtype and mutant MLH3 into HEK293T cells which showed no difference in protein expression, stability, localization or interaction with wildtype MLH1 (Ou_2009_PMID: 19156873). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Glu624 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;.
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;M
MutationTaster
Benign
D;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N;N
REVEL
Benign
Sift
Benign
D;.;T;D
Sift4G
Benign
T;T;T;T
Polyphen
D;D;.;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at