3-37014544-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5PP3_Moderate
The NM_000249.4(MLH1):āc.790C>Gā(p.His264Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000427 in 1,406,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. H264R) has been classified as Pathogenic.
Frequency
Consequence
NM_000249.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250062Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135222
GnomAD4 exome AF: 0.00000427 AC: 6AN: 1406002Hom.: 0 Cov.: 24 AF XY: 0.00000427 AC XY: 3AN XY: 702876
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
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The p.H264D variant (also known as c.790C>G), located in coding exon 9 of the MLH1 gene, results from a C to G substitution at nucleotide position 790. The amino acid change results in histidine to aspartic acid at codon 264, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
This missense variant replaces histidine with aspartic acid at codon 264 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250062 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. -
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:2
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not specified Uncertain:1
Variant summary: MLH1 c.790C>G (p.His264Asp) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250062 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.790C>G has been reported in the literature in at-least one Japanese individual affected with colorectal cancer (example, Kiyozumi_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant(s) have been reported (APC c.994C>T, p.R332*, internal data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5, likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a cohort of cancer patients undergoing genetic testing for Lynch syndrome-related genes (Kiyozumi et al., 2019); This variant is associated with the following publications: (PMID: 30212499, 23760103, 22753075, 31386297) -
Hereditary breast ovarian cancer 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