Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3
The NM_000548.5(TSC2):c.2218A>C(p.Met740Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M740I) has been classified as Likely pathogenic.
TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr16-2072363-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1686682.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.792
Loss of catalytic residue at M740 (P = 0.0185);Loss of catalytic residue at M740 (P = 0.0185);Loss of catalytic residue at M740 (P = 0.0185);.;Loss of catalytic residue at M740 (P = 0.0185);Loss of catalytic residue at M740 (P = 0.0185);Loss of catalytic residue at M740 (P = 0.0185);Loss of catalytic residue at M740 (P = 0.0185);.;Loss of catalytic residue at M740 (P = 0.0185);Loss of catalytic residue at M740 (P = 0.0185);Loss of catalytic residue at M740 (P = 0.0185);Loss of catalytic residue at M740 (P = 0.0185);Loss of catalytic residue at M740 (P = 0.0185);.;