3-37040192-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000249.4(MLH1):c.1565G>A(p.Arg522Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000422 in 1,613,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151930Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251114Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135706
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461104Hom.: 0 Cov.: 30 AF XY: 0.0000385 AC XY: 28AN XY: 726914
GnomAD4 genome AF: 0.0000329 AC: 5AN: 151930Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74174
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
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The MLH1 p.Arg522Gln variant was identified in 2 of 3082 proband chromosomes (frequency: 0.0006) from Dutch and American individuals or families with Lynch syndrome associated cancer or colorectal polyps (Niessen 2006, Yurgelun 2015). A novel bioinformatic prediction model PONMMR (pathogenic-or-not mismatch repair), based on the consensus from the output of 5 tolerance methods, found the variant to be neutral (Ali 2012). The variant was identified in dbSNP (ID: rs63751630) “With Uncertain significance allele”, ClinVar (classified as uncertain significance, reviewed by an expert panel (2013); submitters: uncertain significance by InSIGHT, Invitae, GeneDx, Ambry Genetics, Counsyl, Prevention Genetics and Mendelics; and likely benign by Color), and UMD-LSDB (2X classified as UV). The variant was identified in control databases in 8 of 245844 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 4 of 33554 chromosomes (freq: 0.0001), and European Non-Finnish in 4 of 111384 chromosomes (freq: 0.00004), while not observed in the African, Other, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant was also identified by our laboratory in 1 individual, co-occurring with a pathogenic (familia) MLH1 variant (c.1609C>T,p.Q537X). The p.Arg522 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Gln impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of 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. -
Observed in individuals with breast or other cancers (PMID: 25980754, 35449176, 33471991); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22290698, 25980754, 25085752, 29641532, 32980694, 33471991, 35449176, 36243179, 16636019, 22753075, 12799449, 20533529) -
The frequency of this variant in the general population, 0.00012 (4/34568 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with colorectal cancer, a microsatellite instability-low status, and presence of MLH1 by immunohistochemistry analysis (PMID: 16636019 (2006)), and in a subject suspected of Lynch syndrome (PMID: 25980754 (2015)). It has been reported in individuals with breast cancer as well as in unaffected controls in a large breast cancer association study (PMID: 33471991 (2021), LOVD (http://databases.lovd.nl/shared/genes/MLH1)). However, it has been predicted to be neutral from a consensus-based prediction method (PMID: 22290698 (2012)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:2Benign:1
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: 27363726]. -
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
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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. -
not specified Uncertain:2
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Variant summary: MLH1 c.1565G>A (p.Arg522Gln) results in a conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. A bioinformatic MMR consensus classifier called PON-MMR predicts this variant as having a neutral outcome (Ali_2012). The variant allele was found at a frequency of 3.2e-05 in 251114 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1565G>A has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with colorectal cancer (example, Niessen_2006, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 89791). 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
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Lynch syndrome Uncertain:1
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Hereditary nonpolyposis colorectal neoplasms Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at