rs587778920
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting
The NM_000249.4(MLH1):c.1500_1502delCAT(p.Ile501del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000434 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000249.4 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251478Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135906
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461882Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1Uncertain:2
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Hereditary cancer-predisposing syndrome Uncertain:3
This variant causes an in-frame deletion of 1 amino acid of the MLH1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies showed that this variant protein have wild-type expression level and DNA mismatch repair activity (PMID 29520894). This variant has been reported in 1 individual affected with Lynch Syndrome (PMID 29520894, 28874130). This variant has been identified in 3/251478 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. -
The c.1500_1502delCAT variant (also known as p.I501del) is located in coding exon 13 of the MLH1 gene. This variant results from an in-frame CAT deletion at nucleotide positions 1500 to 1502. This results in the in-frame deletion of an isoleucine at codon 501. This alteration has been reported in a Brazilian female with colorectal cancer at age 60 (Rossi BM et al. Ann Surg Oncol, 2002 Jul;9:555-61). This alteration was identified in an individual diagnosed with an adrenocortical tumor who also carries a TP53 mutation, Arg337His (Brondani VB et al. Cancers (Basel), 2020 Mar;12). This alteration was also detected once in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). Of note, this alteration is also designated as c.1499_1501delTCA in published literature. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear. -
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not provided Uncertain:2
In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Located in the critical region of interaction with EXO1 and PMS2/MLH2/PMS1 (Plotz et al., 2003; Kosinski et al., 2010; Andersen et al., 2012); Published functional studies demonstrate no damaging effect: no significant effect on protein expression levels or mismatch repair activity (Kger et al., 2018); Observed in individuals with colorectal cancer or breast cancer, and co-observed with a pathogenic TP53 variant in a pediatric patient with adrenocortical neoplasm (Rossi et al., 2002; Brondani et al., 2020; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 24344984, 12095971, 28874130, 22753075, 12799449, 20533529, 35264596, 29520894, 32156018) -
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Lynch syndrome Uncertain:1
This variant causes an in-frame deletion of 1 amino acid of the MLH1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies showed that this variant protein have wild-type expression level and DNA mismatch repair activity (PMID 29520894). This variant has been reported in 1 individual affected with Lynch Syndrome (PMID 29520894, 28874130). This variant has been identified in 3/251478 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. -
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