3-37025629-TA-TAA
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1
The NM_000249.4(MLH1):c.1039-6dup variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00061 ( 0 hom., cov: 19)
Exomes 𝑓: 0.00052 ( 1 hom. )
Failed GnomAD Quality Control
Consequence
MLH1
NM_000249.4 splice_region, splice_polypyrimidine_tract, intron
NM_000249.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0980
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 Benign. Variant got -12 ACMG points.
BP6
Variant 3-37025629-T-TA is Benign according to our data. Variant chr3-37025629-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 140797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000606 (82/135212) while in subpopulation AFR AF= 0.00127 (43/33962). AF 95% confidence interval is 0.000966. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 19. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.1039-6dup | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1039-6dup | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000606 AC: 82AN: 135222Hom.: 0 Cov.: 19
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GnomAD3 exomes AF: 0.000153 AC: 18AN: 117468Hom.: 0 AF XY: 0.000133 AC XY: 9AN XY: 67558
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000521 AC: 571AN: 1096034Hom.: 1 Cov.: 20 AF XY: 0.000537 AC XY: 291AN XY: 541536
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GnomAD4 genome AF: 0.000606 AC: 82AN: 135212Hom.: 0 Cov.: 19 AF XY: 0.000566 AC XY: 37AN XY: 65400
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2014 | 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 | Color Diagnostics, LLC DBA Color Health | May 31, 2019 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 07, 2021 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 08, 2020 | - - |
Carcinoma of colon Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MLH1 c.1039-6dupA variant was identified in dbSNP (ID: rs535965616) as “Benign ,Likely benign, Uncertain significance allele”, Clinvitae database (as Benign), ClinVar database (as Benign, by GeneDx, Ambry and Invitae), the 1000 Genomes Project in 239 of 5008 chromosomes (frequency: 0.047), the Exome Aggregation Consortium database (August 8, 2016) in 1441 (49 homozygous) of 43560 chromosomes (frequency: 0.033) in the following populations: African in 282 of 3072 chromosomes (frequency: 0.091), European in 838 of 21102 chromosomes (frequency: 0.039), Finnish in 75 of 2195 chromosomes (frequency: 0.034), East Asian in 80 of 2738 chromosomes (frequency: 0.029), other in 10 of 354 chromosomes (frequency: 0.028), Latino in 60 of 3678 chromosomes (frequency: 0.01.6 x 10-2) and South Asian in 96 of 10422 chromosomes (frequency: 0.0009). This variant was not identified in the literature nor was it identified in COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database, UMD and the NHLBI GO Exome Sequencing Project databases. The c.1039-6dupA variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing; in addition 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 09, 2018 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
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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